Coated capsules and tablets of a fatty acid oil mixture

ABSTRACT

Compositions comprising a fatty acid oil mixture and at least one free fatty acid in a coated capsule or a coated tablet form suitable for oral administration, and methods of use thereof, are disclosed. Further disclosed are preconcentrates comprising a fatty acid oil mixture, at least one surfactant, and optionally at least one free fatty acid, in a coated capsule or a coated tablet form, and methods of use thereof. The preconcentrates are capable of forming a self-nanoemulsifying drug delivery system (SNEDDS), a self-microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery systems (SEDDS) in an aqueous solution.

This application claims priority to U.S. Provisional Application No.61/254,291, filed on Oct. 23, 2009, U.S. Provisional Application No.61/254,293, filed on Oct. 23, 2009, and U.S. Provisional Application No.61/254,296, filed on Oct. 23, 2009, all of which are incorporated hereinby reference in their entireties.

The present disclosure is generally directed to compositions andpreconcentrates comprising a fatty acid oil mixture in a coated capsuleor a coated tablet form suitable for oral administration, and methods ofuse thereof. The capsules and tablets presently disclosed may beadministered to a subject for therapeutic treatment and/or regulation ofat least one health problem including, for example, irregular plasmalipid levels, cardiovascular functions, immune functions, visualfunctions, insulin action, neuronal development, hypertriglyceridemia,hypercholesterolemia, mixed dyslipidemia, heart failure, and postmyocardial infarction (MI).

In humans, cholesterol and triglycerides are part of lipoproteincomplexes in the bloodstream and can be separated viaultracentrifugation into high-density lipoprotein (HDL),intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL),and very-low-density lipoprotein (VLDL) fractions. Cholesterol andtriglycerides are synthesized in the liver, incorporated into VLDL, andreleased into the plasma. High levels of total cholesterol (total-C),LDL-C, and apolipoprotein B (a membrane complex for LDL-C and VLDL-C)promote human atherosclerosis and decreased levels of HDL-C and itstransport complex; apolipoprotein A is also associated with thedevelopment of atherosclerosis. Furthermore, cardiovascular morbidityand mortality in humans can vary directly with the level of total-C andLDL-C and inversely with the level of HDL-C. In addition, researchsuggests that non-HDL cholesterol is an indicator ofhypertriglyceridemia, vascular disease, atherosclerotic disease, andrelated conditions. In fact, NCEP ATP III specifies non-HDL cholesterolreduction as a treatment objective.

Omega-3 fatty acids may regulate plasma lipid levels, cardiovascular andimmune functions, insulin action, and neuronal development, and visualfunction. Marine oils, also commonly referred to as fish oils, are asource of omega-3 fatty acids, including eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), have been found to regulate lipidmetabolism. Plant-based oils and microbial oils are also sources ofomega-3 fatty acids. Omega-3 fatty acids may have beneficial effects onthe risk factors for cardiovascular diseases, for example hypertensionand hypertriglyceridemia, and on the coagulation factor VII phospholipidcomplex activity. Omega-3 fatty acids may also lower serumtriglycerides, increase serum HDL cholesterol, lower systolic anddiastolic blood pressure and/or pulse rate, and may lower the activityof the blood coagulation factor VII-phospholipid complex. Further,omega-3 fatty acids are generally well-tolerated, without giving rise tosevere side effects.

Several formulations of omega-3 fatty acids have been developed. Forexample, one form of omega-3 fatty acid oil mixture is a concentrate ofprimary omega-3, long chain, polyunsaturated fatty acids from fish oilcontaining DHA and EPA, such as sold under the trademarkOmacor®/Lovaza™/Zodin™/Seacor®. See, for example, U.S. Pat. Nos.5,502,077, 5,656,667, 5,698,594, and 7,732,488. In particular, each 1000mg capsule of Lovaza™ contains at least 90% omega-3 ethyl ester fattyacids (84% EPA/DHA); approximately 465 mg EPA ethyl ester andapproximately 375 mg DHA ethyl ester.

However, evidence suggests that long chain fatty acids and alcohols ofup to at least C₂₄ are reversibly interconverted. Enzyme systems existin the liver, fibroblasts, and the brain that convert fatty alcohols tofatty acids. In some tissues, fatty acids can be reduced back toalcohols. The carboxylic acid functional group of fatty acid moleculestargets binding, but this ionizable group may hinder the molecule fromcrossing the cell membranes, such as of the intestinal wall. As aresult, carboxylic acid functional groups are often protected as esters.The ester is less polar than the carboxylic acid, and may more easilycross the fatty cell membranes. Once in the bloodstream, the ester canbe hydrolyzed back to the free carboxylic acid by enzyme esterase in theblood. It may be possible that the plasma enzymes do not hydrolyze theester fast enough, however, and that the conversion of ester to freecarboxylic acid predominantly takes place in the liver. Ethyl esters ofpolyunsaturated fatty can also be hydrolyzed to free carboxylic acids invivo.

Thus, there remains a need in the art for compositions and/or methods toimprove the release and enhance solubilization, digestion,bioavailability and/or absorption of omega-3 fatty acids in vivo, whilemaintaining the ability to cross cell membranes.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the present disclosure, as claimed.

The present disclosure is directed to a pharmaceutical composition in agelatin capsule or a tablet form comprising: a fatty acid oil mixturecomprising at least 75% eicosapentaenoic acid (EPA) and docosahexaenoicacid (DHA), by weight of the fatty acid oil mixture, wherein the EPA andDHA are in a form chosen from ethyl ester and triglyceride; and at leastone free fatty acid; wherein the gelatin capsule or the tablet comprisesat least one coating.

The present disclosure is also directed to a food supplement ornutritional supplement composition in a gelatin capsule or a tablet formcomprising: a fatty acid oil mixture comprising from about 25% to about75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), byweight of the fatty acid oil mixture, wherein the EPA and DHA are in aform chosen from ethyl ester and triglyceride; and at least one freefatty acid; wherein the gelatin capsule or the tablet comprises at leastone coating.

The present disclosure is also directed to pharmaceutical preconcentratea gelatin capsule or a tablet form comprising: a fatty acid oil mixturecomprising at least 75% eicosapentaenoic acid (EPA) and docosahexaenoicacid (DHA), by weight of the fatty acid oil mixture, wherein the EPA andDHA are in a form chosen from ethyl ester, triglyceride; at least onefree fatty acid; and at least one surfactant; wherein the gelatincapsule or the tablet comprises at least one coating.

The present disclosure is also directed to a pharmaceuticalpreconcentrate in a gelatin capsule or a tablet form comprising: fromabout 45% to about 55% by weight, relative to the weight of thepreconcentrate, of a fatty acid oil mixture comprising from about 80% toabout 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) byweight of the fatty acid oil mixture, wherein the EPA and DHA are inethyl ester form; from about 10% to about 15% by weight, relative to theweight of the preconcentrate, of at least one free fatty acid comprisingfrom about 80% to about 88% EPA and DHA, by weight of the at least onefree fatty acid, wherein the EPA and DHA are in free fatty acid form;and from about 30% to about 40% by weight, relative to the weight of thepreconcentrate, of at least one surfactant chosen from polysorbate 20;wherein the gelatin capsule or the tablet comprises at least onecoating.

The present disclosure is also directed to a pharmaceuticalpreconcentrate in a gelatin capsule or a tablet form comprising: fromabout 45% to about 55% by weight, relative to the weight of thepreconcentrate, of a fatty acid oil mixture comprising from about 80% toabout 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) byweight of the fatty acid oil mixture, wherein the EPA and DHA are inethyl ester form; from about 10% to about 15% by weight, relative to theweight of the preconcentrate, of at least one free fatty acid chosenfrom oleic acid; and from about 30% to about 40% by weight, relative tothe weight of the preconcentrate, of at least one surfactant chosen frompolysorbate 20; wherein the gelatin capsule or the tablet comprises atleast one coating.

The present disclosure is also directed to a pharmaceuticalpreconcentrate in a gelatin capsule or a tablet form comprising: fromabout 65% to about 75% by weight, relative to the weight of thepreconcentrate, of a fatty acid oil mixture comprising from about 80% toabout 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) byweight of the fatty acid oil mixture, wherein the EPA and DHA are inethyl ester form; from about 15% to about 20% by weight, relative to theweight of the preconcentrate, of at least one free fatty acid chosenfrom oleic acid; and from about 10% to about 15% by weight, relative tothe weight of the preconcentrate, of at least one surfactant chosen frompolysorbate 20; wherein the gelatin capsule or the tablet comprises atleast one coating.

The present disclosure is also directed to a pharmaceuticalpreconcentrate in a gelatin capsule or a tablet form comprising: fromabout 45% to about 55% by weight, relative to the weight of thepreconcentrate, of a fatty acid oil mixture comprising from about 80% toabout 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) byweight of the fatty acid oil mixture, wherein the EPA and DHA are inethyl ester form; from about 10% to about 15% by weight, relative to theweight of the preconcentrate, of at least one free fatty acid comprisingfrom about 80% to about 88% EPA and DHA, by weight of the at least onefree fatty acid, wherein the EPA and DHA are in free fatty acid form;and from about 40% to about 50% by weight, relative to the weight of thepreconcentrate, of at least two surfactants chosen from polysorbate 20and lecithin; wherein the gelatin capsule or the tablet comprises atleast one coating.

The present disclosure is also directed to a pharmaceuticalpreconcentrate in a gelatin capsule or a tablet form comprising: a fattyacid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), by weight of the fatty acid oil mixture,wherein the EPA and DHA are in free acid form; and at least onesurfactant; wherein the gelatin capsule or the tablet comprises at leastone coating.

The present disclosure is also directed to a pharmaceuticalpreconcentrate in a gelatin capsule or a tablet form comprising: fromabout 60% to about 70% by weight, relative to the weight of thepreconcentrate, of a fatty acid oil mixture comprising from about 80% toabout 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), byweight of the fatty acid oil mixture, wherein the EPA and DHA are infree acid form; and from about 30% to about 40% by weight, relative tothe weight of the preconcentrate, of at least two surfactants chosenfrom polysorbate 20 and lecithin; wherein the gelatin capsule or thetablet comprises at least one coating.

The present disclosure is also directed to a pharmaceuticalpreconcentrate in a gelatin capsule or a tablet form comprising: a fattyacid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), by weight of the fatty acid oil mixture,wherein the EPA and DHA are in a form chosen from ethyl ester andtriglyceride; and at least one surfactant; wherein the gelatin capsuleor the tablet comprises at least one coating.

The present disclosure is also directed to a pharmaceuticalpreconcentrate in a gelatin capsule or a tablet form comprising: fromabout 75% to about 85% by weight, relative to the weight of thepreconcentrate, of a fatty acid oil mixture comprising from about 80% toabout 88% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) byweight of the fatty acid oil mixture, wherein the EPA and DHA are inethyl ester form; and from about 15% to about 25% by weight, relative tothe weight of the preconcentrate, of at least one surfactant chosen frompolysorbate 80; wherein the gelatin capsule or the tablet comprises atleast one coating.

The present disclosure is also directed to a food supplement ornutritional supplement preconcentrate in a gelatin capsule or a tabletform comprising: a fatty acid oil mixture comprising from about 25% toabout 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), byweight of the fatty acid oil mixture, wherein the EPA and DHA are in aform chosen from ethyl ester and triglyceride; at least one free fattyacid; and at least one surfactant; wherein the gelatin capsule or thetablet comprises at least one coating.

The present disclosure is also directed to a food supplementpreconcentrate or nutritional supplement preconcentrate in a gelatincapsule or a tablet form comprising: a fatty acid oil mixture comprisingfrom about 25% to about 75% eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), by weight of the fatty acid oil mixture,wherein the EPA and DHA are in free acid form; and at least onesurfactant; wherein the gelatin capsule or the tablet comprises at leastone coating.

The present disclosure is also directed to a food supplementpreconcentrate or nutritional supplement preconcentrate in a gelatincapsule or a tablet form comprising: a fatty acid oil mixture comprisingfrom about 25% to about 75% eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), by weight of the fatty acid oil mixture,wherein the EPA and DHA are in a form chosen from ethyl ester andtriglyceride; and at least one surfactant; and wherein the gelatincapsule or the tablet comprises at least one coating.

The present disclosure is also directed to a pharmaceutical compositionin a gelatin capsule or a tablet form comprising a fatty acid oilmixture comprising at least 75% eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), by weight of the fatty acid oil mixture,wherein the EPA and DHA are in a form chosen from ethyl ester andtriglyceride, and at least one free fatty acid, wherein the gelatincapsule or the tablet comprises at least one coating, for the treatmentof at least one health problem chosen from irregular plasma lipidlevels, cardiovascular functions, immune functions, visual functions,insulin action, neuronal development, heart failure, and post myocardialinfarction.

The present disclosure is also directed to a pharmaceuticalpreconcentrate in a gelatin capsule or a tablet form comprising a fattyacid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), by weight of the fatty acid oil mixture,wherein the EPA and DHA are in a form chosen from ethyl ester andtriglyceride, at least one free fatty acid, and at least one surfactant,wherein the gelatin capsule or the tablet comprises at least onecoating, for the treatment of at least one health problem chosen fromirregular plasma lipid levels, cardiovascular functions, immunefunctions, visual functions, insulin action, neuronal development, heartfailure, and post myocardial infarction.

The present disclosure is also directed to a self-nanoemulsifying drugdelivery system (SNEDDS), self-microemulsifying drug delivery system(SMEDDS), or self-emulsifying drug delivery system (SEDDS) comprising apharmaceutical preconcentrate in a gelatin capsule or a tablet formcomprising: a fatty acid oil mixture comprising at least 75%eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight ofthe fatty acid oil mixture, wherein the EPA and DHA are in a form chosenfrom ethyl ester and triglyceride, at least one free fatty acid, and atleast one surfactant, wherein the gelatin capsule or the tabletcomprises at least one coating, and wherein the preconcentrate forms anemulsion in an aqueous solution, for the treatment of at least onehealth problem chosen from irregular plasma lipid levels, cardiovascularfunctions, immune functions, visual functions, insulin action, neuronaldevelopment, heart failure, and post myocardial infarction.

The present disclosure is also directed to a pharmaceuticalpreconcentrate in a gelatin capsule or a tablet form comprising a fattyacid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), by weight of the fatty acid oil mixture,wherein the EPA and DHA are in free acid form and at least onesurfactant, wherein the gelatin capsule or the tablet comprises at leastone coating, for the treatment of at least one health problem chosenfrom irregular plasma lipid levels, cardiovascular functions, immunefunctions, visual functions, insulin action, neuronal development, heartfailure, and post myocardial infarction.

The present disclosure is also directed to a self-nanoemulsifying drugdelivery system (SNEDDS), self-microemulsifying drug delivery system(SMEDDS), or self-emulsifying drug delivery system (SEDDS) comprising apharmaceutical preconcentrate comprising: a fatty acid oil mixturecomprising at least 75% eicosapentaenoic acid (EPA) and docosahexaenoicacid (DHA), by weight of the fatty acid oil mixture, wherein the EPA andDHA are in free acid form and at least one surfactant, wherein thegelatin capsule or the tablet comprises at least one coating, andwherein the preconcentrate forms an emulsion in an aqueous solution, forthe treatment of at least one health problem chosen from irregularplasma lipid levels, cardiovascular functions, immune functions, visualfunctions, insulin action, neuronal development, heart failure, and postmyocardial infarction.

The present disclosure is also directed to a pharmaceuticalpreconcentrate in a gelatin capsule or a tablet form comprising a fattyacid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), by weight of the fatty acid oil mixture,wherein the EPA and DHA are in a form chosen from ethyl ester andtriglyceride and at least one surfactant, wherein the gelatin capsule orthe tablet comprises at least one coating, for the treatment of at leastone health problem chosen from irregular plasma lipid levels,cardiovascular functions, immune functions, visual functions, insulinaction, neuronal development, heart failure, and post myocardialinfarction.

The present disclosure is also directed to a self-nanoemulsifying drugdelivery system (SNEDDS), self-microemulsifying drug delivery system(SMEDDS), or self-emulsifying drug delivery system (SEDDS) comprising apharmaceutical preconcentrate comprising: a fatty acid oil mixturecomprising at least 75% eicosapentaenoic acid (EPA) and docosahexaenoicacid (DHA), by weight of the fatty acid oil mixture, wherein the EPA andDHA are in a form chosen from ethyl ester and triglyceride, and at leastone surfactant, wherein the gelatin capsule or the tablet comprises atleast one coating, and wherein the preconcentrate forms an emulsion inan aqueous solution, for the treatment of at least one health problemchosen from irregular plasma lipid levels, cardiovascular functions,immune functions, visual functions, insulin action, neuronaldevelopment, heart failure, and post myocardial infarction.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the viscosity of preconcentrates A-L.

FIG. 2 shows the average particle size distribution for preconcentratesA-F, I, and J in gastric media and intestinal media.

FIG. 3 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate A in gastric media.

FIG. 4 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate B in gastric media.

FIG. 5 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate C in gastric media.

FIG. 6 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate D in gastric media.

FIG. 7 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate E in gastric media.

FIG. 8 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate F in gastric media.

FIG. 9 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate I in gastric media.

FIG. 10 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate J in gastric media.

FIG. 11 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate A in intestinal media.

FIG. 12 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate B in intestinal media.

FIG. 13 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate C in intestinal media.

FIG. 14 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate D in intestinal media.

FIG. 15 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate E in intestinal media.

FIG. 16 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate F in intestinal media.

FIG. 17 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate I in intestinal media.

FIG. 18 shows the read out from the Malvern zetasizer for fourconsecutive measurements on preconcentrate J in intestinal media.

FIG. 19 shows the disappearance of EPA-EE and DHA-EE and the appearanceof EPA-FA and DHA-FA during lipolysis of Omacor®.

FIG. 20 shows the percent recovery of EPA+DHA at different time-pointsfor Omacor®.

FIG. 21 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE atdifferent time points for Omacor®.

FIG. 22 shows the disappearance of EPA-EE and DHA-EE and the appearanceof EPA-FA and DHA-FA during lipolysis of preconcentrate A.

FIG. 23 shows the percent recovery of EPA+DHA at different time-pointsfor preconcentrate A.

FIG. 24 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE atdifferent time points for preconcentrate A.

FIG. 25 shows the disappearance of EPA-EE and DHA-EE and the appearanceof EPA-FA and DHA-FA during lipolysis of preconcentrate B.

FIG. 26 shows the percent recovery of EPA+DHA at different time-pointsfor preconcentrate B.

FIG. 27 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE atdifferent time points for preconcentrate B.

FIG. 28 shows the disappearance of EPA-EE and DHA-EE and the appearanceof EPA-FA and DHA-FA during lipolysis of preconcentrate C.

FIG. 29 shows the percent recovery of EPA+DHA at different time-pointsfor preconcentrate C.

FIG. 30 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE atdifferent time points for preconcentrate C.

FIG. 31 shows the disappearance of EPA-EE and DHA-EE and the appearanceof EPA-FA and DHA-FA during lipolysis of preconcentrate D.

FIG. 32 shows the percent recovery of EPA+DHA at different time-pointsfor preconcentrate D.

FIG. 33 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE atdifferent time points for preconcentrate D.

FIG. 34 shows the disappearance of EPA-EE and DHA-EE and the appearanceof EPA-FA and DHA-FA during lipolysis of preconcentrate E.

FIG. 35 shows the percent recovery of EPA+DHA at different time-pointsfor preconcentrate E.

FIG. 36 shows the percent lipolysis of EPA-EE, DHA-EE and total K85EE atdifferent time points for preconcentrate E.

FIG. 37 shows the plasma concentration versus time profile of the totallipid concentration of EPA for Example 14.

FIG. 38 shows EPA blood serum level over time following theadministration of coated and uncoated tablets as described in Example22.

FIG. 39 shows DHA blood serum level over time following theadministration of coated and uncoated tablets as described in Example22.

DESCRIPTION

Particular aspects of the disclosure are described in greater detailbelow. The terms and definitions as used in the present application andas clarified herein are intended to represent the meaning within thepresent disclosure. The patent and scientific literature referred toherein and referenced above is hereby incorporated by reference. Theterms and definitions provided herein control, if in conflict with termsand/or definitions incorporated by reference.

The singular forms “a,” “an,” and “the” include plural reference unlessthe context dictates otherwise.

The terms “approximately” and “about” mean to be nearly the same as areferenced number or value. As used herein, the terms “approximately”and “about” should be generally understood to encompass±10% of aspecified amount, frequency or value.

The terms “administer,” “administration” or “administering” as usedherein refer to (1) providing, giving, dosing and/or prescribing byeither a health practitioner or his authorized agent or under hisdirection a composition according to the disclosure, and (2) puttinginto, taking or consuming by the patient or person himself or herself, acomposition according to the disclosure.

The present disclosure provides for pharmaceutical and supplementcompositions comprising a fatty acid oil mixture and at least one freefatty acid formulated as capsules, e.g., gelatin capsules, and tabletsthat may be coated.

Also disclosed herein are preconcentrates comprising a fatty acid oilmixture and at least one surfactant. In some embodiments, thepreconcentrates comprise a fatty acid oil mixture, at least one freefatty acid, and at least one surfactant. The preconcentrates of thepresent disclosure can produce dispersions of low or very low meanparticle size when mixed with an aqueous medium. Such dispersions can becharacterized as nanoemulsions, microemulsions, or emulsions. Forexample, upon delivery, the preconcentrates are thought to producedispersions with gastric or other physiological fluids generatingself-nanoemulsifying drug delivery systems (SNEDDS),self-microemulsifying drug delivery systems (SMEDDS), or selfemulsifying drug delivery systems (SEDDS).

Fatty Acid Oil Mixture

Compositions of the present disclosure comprise at least one fatty acidoil mixture. The fatty acid oil mixture comprises eicosapentaenoic acid(EPA) and docosahexaenoic acid (DHA). As used herein, the term “fattyacid oil mixture” includes fatty acids, such as unsaturated (e.g.,monounsaturated, polyunsaturated) or saturated fatty acids, as well aspharmaceutically-acceptable esters, free acids, mono-, di- andtriglycerides, derivatives, conjugates, precursors, salts, and mixturesthereof. In some embodiments, the fatty acid oil mixture comprises fattyacids, such as omega-3 fatty acids, in a form chosen from ethyl esterand triglyceride. In other embodiments, the fatty acids of the fattyacid oil mixture are in free acid form.

The term “omega-3 fatty acids” includes natural and synthetic omega-3fatty acids, as well as pharmaceutically-acceptable esters, free acids,triglycerides, derivatives, conjugates (see, e.g., Zaloga et al., U.S.Patent Application Publication No. 2004/0254357, and Horrobin et al.,U.S. Pat. No. 6,245,811, each hereby incorporated by reference),precursors, salts, and mixtures thereof. Examples of omega-3 fatty acidoils include, but are not limited to, omega-3 polyunsaturated,long-chain fatty acids such as eicosapentaenoic acid (EPA),docosahexaenoic acid (DHA), α-linolenic acid (ALA), heneicosapentaenoicacid (HPA), docosapentaenoic acid (DPA), eicosatetraenoic acid (ETA),eicosatrienoic acid (ETE), and octadecatetraenoic acid (i.e.,stearidonic acid, STA); esters of omega-3 fatty acids with glycerol suchas mono-, di- and triglycerides; and esters of the omega-3 fatty acidsand a primary, secondary and/or tertiary alcohol, such as, for example,fatty acid methyl esters and fatty acid ethyl esters. The omega-3 fattyacids, esters, triglycerides, derivatives, conjugates, precursors, saltsand/or mixtures thereof according to the present disclosure can be usedin their pure form and/or as a component of an oil, for example, asmarine oil (e.g., fish oil and purified fish oil concentrates), algaeoils, microbial oils and plant-based oils.

In some embodiments of the present disclosure, the fatty acid oilmixture comprises EPA and DHA. Further for example, in some embodiments,the fatty acid oil mixture comprises EPA and DHA in a form chosen fromethyl ester and triglyceride. In other embodiments, the fatty acid oilmixture comprises EPA and DHA in free acid form.

The fatty acid oil mixture of the present disclosure may furthercomprise at least one fatty acid other than EPA and DHA. Examples ofsuch fatty acids include, but are not limited to, omega-3 fatty acidsother than EPA and DHA and omega-6 fatty acids. For example, in someembodiments of the present disclosure, the fatty acid oil mixturecomprises at least one fatty acid other than EPA and DHA chosen fromα-linolenic acid (ALA), heneicosapentaenoic acid (HPA), docosapentaenoicacid (DPA), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), andstearidonic acid (STA). In some embodiments, the at least one fatty acidother than EPA and DHA is chosen from linoleic acid, gamma-linolenicacid (GLA), arachidonic acid (AA), docosapentaenoic acid (i.e., osbondacid), and mixtures thereof. In some embodiments, the at least one fattyacid other than EPA and DHA is in a form chosen from ethyl ester andtriglyceride. In other embodiments, the at least one fatty acid otherthan EPA and DHA is in free acid form.

Examples of further fatty acids, or mixtures thereof (fatty acid oilmixtures) encompassed by the present disclosure include, but are notlimited to, the fatty acids defined in the European PharmacopoeiaOmega-3 Ethyl Esters 90 and purified marine oils, for example, theEuropean Pharmacopoeia Omega-3 Acid Triglycerides, the EuropeanPharmacopoeia Omega-3 acid Ethyl Esters 60, the European PharmacopoeiaFish Oil Rich in Omega-3 Acids monograph, and/or for instance, the USPfish oil monograph.

Commercial examples of fatty acid oil mixtures comprising differentfatty acids suitable for the present disclosure include, but are notlimited to: Incromega™ omega-3 marine oil concentrates such asIncromega™ TG7010 SR, Incromega™ E7010 SR, Incromega™ TG6015, Incromega™EPA500TG SR, Incromega™ E400200 SR, Incromega™ E4010, Incromega™DHA700TG SR, Incromega™ DHA700E SR, Incromega™ DHA500TG SR, Incromega™TG3322 SR, Incromega™ E3322 SR, Incromega™ TG3322, Incromega™ E3322,Incromega™ Trio TG/EE (Croda International PLC, Yorkshire, England);EPAX2050TG, EPAX5500EE, EPAX5500TG, EPAX5000EE, EPAX5000TG, EPAX6000EE,EPAX6000TG, EPAX6000FA, EPAX6500EE, EPAX6500TG, EPAX4510TG, EPAX1050TG,EPAX6015TG/EE, EPAX4020TG, and EPAX4020EE (EPAX is a wholly-ownedsubsidiary of Norwegian company Austevoll Seafood ASA);Omacor®/Lovaza™/Zodin®/Seacor® finished pharmaceutical product, K85EE,and AGP 103 (Pronova BioPharma Norge AS); MEG-3® EPA/DHA fish oilconcentrates (Ocean Nutrition Canada); DHA FNO “Functional NutritionalOil” and DHA CL “Clear Liquid” (Lonza); Superba™ Krill Oil (Aker);omega-3 products comprising DHA produced by Martek; Neptune krill oil(Neptune); cod-liver oil products and anti-reflux fish oil concentrate(TG) produced by Møllers; Lysi Omega-3 Fish oil; Seven Seas Triomega®Cod Liver Oil Blend (Seven Seas); Fri Flyt Omega-3 (Vesterálens); andEpadel (Mochida). Those commercial embodiments provide for variousomega-3 fatty acids, combinations, and other components as a result ofthe transesterification process or method of preparation in order toobtain the omega-3 fatty acid(s) from various sources, such as marine,algae, microbial, and plant-based sources.

The fatty acid oil mixture according to the present disclosure may bederived from animal oils and/or non-animal oils. In some embodiments ofthe present disclosure, the fatty acid oil mixture is derived from atleast one oil chosen from marine oil, algae oil, plant-based oil, andmicrobial oil. Marine oils include, for example, fish oil, krill oil,and lipid composition derived from fish. Plant-based oils include, forexample, flaxseed oil, canola oil, mustard seed oil, and soybean oil.Microbial oils include, for example, products by Martek. In at least oneembodiment of the present disclosure, the fatty acid oil mixture isderived from a marine oil, such as a fish oil. In at least oneembodiment, the marine oil is a purified fish oil.

In some embodiments of the present disclosure, the fatty acids, such asomega-3 fatty acids, of the fatty acid oil mixture are esterified, suchas alkyl esters. The alkyl esters may include, but are not limited to,ethyl, methyl, propyl, and butyl esters, and mixtures thereof. In otherembodiments, the fatty acids are chosen from mono-, di-, andtriglycerides.

In some embodiments, the fatty acid oil mixture is obtained by atransesterification of the body oil of a fat fish species coming from,for example, anchovy or tuna oil, and subsequent physico-chemicalpurification processes, including urea fractionation followed bymolecular distillation. In some embodiments, the crude oil mixture mayalso be subjected to a stripping process for decreasing the amount ofenvironmental pollutants and/or cholesterol before thetransesterification.

In another embodiment, the fatty acid oil mixture is obtained by usingsupercritical CO₂ extraction or chromatography techniques, for example,to up-concentrate primary EPA and DHA from fish oil concentrates.Commercial embodiments of fatty acids in ethyl triglyceride formencompassed by the present disclosure include, but are not limited to,K85TG (Pronova BioPharma Norge AS). Commercial embodiments of fattyacids in ethyl ester form encompassed by the present disclosure include,but are not limited to, K85EE (Pronova BioPharma Norge AS).

In another embodiment, the fatty acid oil mixture is obtained byhydrolyzing a fatty acid oil mixture in ethyl ester form. Commercialembodiments of fatty acids in free acid form encompassed by the presentdisclosure include, but are not limited to, K85FA (Pronova BioPharmaNorge AS).

In some embodiments of the present disclosure, at least one of theomega-3 fatty acids of the fatty acid oil mixture has a cisconfiguration. Examples include, but are not limited to,(all-Z)-9,12,15-octadecatrienoic acid (ALA),(all-Z)-6,9,12,15-octadecatetraenoic acid (STA),(all-Z)-11,14,17-eicosatrienoic acid (ETE),(all-Z)-5,8,11,14,17-eicosapentaenoic acid (EPA),(all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA),(all-Z)-8,11,14,17-eicosatetraenoic acid (ETA),(all-Z)-7,10,13,16,19-docosapentaenoic acid (DPA),(all-Z)-6,9,12,15,19-heneicosapentaenoic acid (HPA);(all-Z)-5,8,11,14-eicosatetraenoic acid,(all-Z)-4,7,10,13,16-docosapentaenoic acid (osbond acid),(all-Z)-9,12-octadecadienoic acid (linoleic acid),(all-Z)-5,8,11,14-eicosatetraenoic acid (AA),(all-Z)-6,9,12-octadecatrienoic acid (GLA); (Z)-9-octadecenoic acid(oleic acid), 13(Z)-docosenoic acid (erucic acid),(R-(Z))-12-hydroxy-9-octadecenoic acid (ricinoleic acid).

In some embodiments of the present disclosure, the weight ratio ofEPA:DHA of the fatty acid oil mixture ranges from about 1:10 to about10:1, from about 1:8 to about 8:1, from about 1:6 to about 6:1, fromabout 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 toabout 3:1, or from about 1:2 to 2 about :1. In at least one embodiment,the weight ratio of EPA:DHA of the fatty acid oil mixture ranges fromabout 1:2 to about 2:1. In at least one embodiment, the weight ratio ofEPA:DHA of the fatty acid oil mixture ranges from about 1:1 to about2:1. In at least one embodiment, the weight ratio of EPA:DHA of thefatty acid oil mixture ranges from about 1.2 to about 1.3.

In some embodiments of the present disclosure, the compositions and/orpreconcentrates comprise one or more fatty acids, or mixtures thereof,in free acid form. Without being bound by theory, it is believed thatfatty acids in free acid form may enhance or improve lipolysis in thebody. For example, the addition of at least one fatty acid in free acidform may enhance or improve interconversion of fatty acid esters and/ortriglycerides to the free fatty acid form for efficient uptake. Freefatty acids may, for example, provide for enhanced or improvedhydrolysis, solubility, bioavailability, absorption, or any combinationsthereof of fatty acids in vivo.

Examples of free fatty acids include, but are not limited to,polyunsaturated fatty acids such as EPA, DHA, α-linolenic acid (ALA),heneicosapentaenoic acid (HPA), docosapentaenoic acid (DPA),eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), stearidonic acid(STA), linoleic acid, gamma-linolenic acid (GLA), arachidonic acid (AA),osbond acid, oleic acid, ricinoleic acid, erucic acid, and mixturesthereof, in free acid form.

In some embodiments of the present disclosure, the compositions comprisea fatty acid oil mixture in a form chosen from ethyl ester andtriglyceride and at least one free fatty acid, such as at least one freefatty acid comprising at least 80% omega-3 fatty acids by weight of theat least one free fatty acid, such as at least 90% omega-3 fatty acidsby weight of the at least one free fatty acid. In some embodiments, thecompositions comprise a fatty acid oil mixture in a form chosen fromethyl ester and triglyceride and at least one free fatty acid is chosenfrom oleic acid, ricinoleic acid, linoleic acid, and erucic acid. In oneembodiment, the at least one free fatty acid comprises oleic acid orlinoleic acid.

In some embodiments, the at least one free fatty acid comprises at least75% EPA and DHA by weight of the at least one free fatty acid. Forexample, in some embodiments, the at least one free fatty acid comprisesat least 80% by weight, at least 85% by weight, at least 90% by weight,or at least 95% EPA and DHA, by weight of the at least one free fattyacid. In some embodiments, the at least one free fatty acid comprisesabout 80% EPA and DHA by weight of the at least one free fatty acid,such as about 85%, about 90%, about 95%, or any number in between, byweight of the at least one free fatty acid. The at least one free fattyacid can be used in a pure form and/or as a component of an oil, forexample, as marine oil (e.g., fish oil and purified fish oilconcentrates), microbial oil and plant-based oils.

In some embodiments, the at least one free fatty acid comprises fromabout 75% to about 95% EPA and DHA by weight of the at least one freefatty acid, such as from about 75% to about 90%, from about 75% to about85%, from about 75% to about 80%, from about 80% to about 95%, fromabout 80% to about 90%, from about 80% to about 85%, from about 85% toabout 95%, from about 85% to about 90%, and further for example, fromabout 90% to about 95% by weight of the at least one free fatty acid, orany number in between. In at least one embodiment, the at least one freefatty acid comprises from about 80% to about 85% EPA and DHA, by weightof the at least one free fatty acid, such as from about 80% to about 88%EPA and DHA by weight, such as about 84%, by weight of the at least onefree fatty acid.

Pharmaceutical

In some embodiments of the present disclosure, the fatty acid oilmixture acts as an active pharmaceutical ingredient (API). In someembodiments, the fatty acid oil mixture is present in apharmaceutically-acceptable amount. As used herein, the term“pharmaceutically-effective amount” means an amount sufficient to treat,e.g., reduce and/or alleviate the effects, symptoms, etc., at least onehealth problem in a subject in need thereof. In at least someembodiments of the present disclosure, the fatty acid oil mixture doesnot comprise an additional active agent.

Where the composition is a pharmaceutical composition, the fatty acidoil mixture comprises at least 75% EPA and DHA by weight of the fattyacid oil mixture. For example, in one embodiment, the fatty acid oilmixture comprises at least 80% EPA and DHA by weight of the fatty acidoil mixture, such as at least 85%, at least 90%, or at least 95%, byweight of the fatty acid oil mixture. In some embodiments, the fattyacid oil mixture comprises about 80% EPA and DHA by weight of the fattyacid oil mixture, such as about 85%, about 90%, about 95%, or any numberin between, by weight of the fatty acid oil mixture.

For example, in some embodiments, the fatty acid oil mixture comprisesfrom about 75% to about 95% EPA and DHA by weight of the fatty acid oilmixture, such as from about 75% to about 90%, from about 75% to about88%, from about 75% to about 85%, from about 75% to about 80%, fromabout 80% to about 95%, from about 80% to about 90%, from about 80% toabout 85%, from about 85% to about 95%, from about 85% to about 90%, andfurther for example, from about 90% to about 95% EPA and DHA, by weightof the fatty acid oil mixture, or any number in between. In at least oneembodiment, the fatty acid oil mixture comprises from about 80% to about85% EPA and DHA, by weight of the fatty acid oil mixture, such as fromabout 80% to about 88%, such as about 84%, by weight of the fatty acidoil mixture.

In some embodiments, the fatty acid oil mixture comprises at least 95%of EPA or DHA, or EPA and DHA, by weight of the fatty acid oil mixture.

In a further embodiment, the fatty acid oil mixture may comprise otheromega-3 fatty acids. For example, the present disclosure encompasses atleast 90% omega-3 fatty acids, by weight of the fatty acid oil mixture.

In one embodiment, for example, the fatty acid oil mixture comprisesfrom about 75% to about 88% EPA and DHA, by weight of the fatty acid oilmixture, wherein the fatty acid oil mixture comprises at least 90% ofomega-3 fatty acids, by weight of the fatty acid oil mixture.

In another embodiment, the fatty acid oil mixture comprises from about75% to about 88% EPA and DHA, by weight of the fatty acid oil mixture,wherein the fatty acid oil mixture comprises at least 90% of omega-3fatty acids, by weight of the fatty acid oil mixture, and wherein thefatty acid oil mixture comprises α-linolenic acid (ALA).

In one embodiment, the fatty acid oil mixture comprises from about 80%to about 88% EPA and DHA by weight of the fatty acid oil mixture, andfurther comprises docosapentaenoic acid (DPA).

In another embodiment, the fatty acid oil mixture comprises from about80% to about 88% EPA and DHA by weight of the fatty acid oil mixture,and further comprises from about 1% to about 4% (all-Zomega-3)-6,9,12,15,18-heneicosapentaenoic acid (HPA), by weight of thefatty acid oil mixture.

In another embodiment, the fatty acid oil mixture comprises from about80% to about 88% EPA and DHA by weight of the fatty acid oil mixture;and from 1% to about 4% fatty acids other than EPA and DHA, by weight ofthe fatty acid oil mixture, wherein the fatty acids other than EPA andDHA have C₂₀, C₂₁, or C₂₂ carbon atoms.

In one embodiment, the fatty acid oil mixture may comprise K85EE or AGP103 (Pronova BioPharma Norge AS). In another embodiment, the fatty acidoil mixture may comprise K85TG (Pronova BioPharma Norge AS). In yetanother embodiment, the fatty acid oil mixture may comprise K85FA(BioPharma Norge AS).

In some embodiments of the present disclosure, the pharmaceuticalcompositions provide for enhanced bioavailability, such as greater thanabout 40% increase in bioavailability, such as, about 80% increase.

EPA and DHA Products

In at least one embodiment, the fatty acid oil mixture comprises atleast 75% EPA and DHA by weight of the fatty acid oil mixture, of whichat least 95% is EPA. In another embodiment, the fatty acid oil mixturecomprises at least 80% EPA and DHA by weight of the fatty acid oilmixture, of which at least 95% is EPA. In yet another embodiment, thefatty acid oil mixture comprises at least 90% EPA and DHA by weight ofthe fatty acid oil mixture, of which at least 95% is EPA.

In another embodiment, the fatty acid oil mixture comprises at least 75%EPA and DHA by weight of the fatty acid oil mixture, of which at least95% is DHA. For example, in one embodiment, the fatty acid oil mixturecomprises at least 80% EPA and DHA by weight of the fatty acid oilmixture, of which at least 95% is DHA. In another embodiment, the fattyacid oil mixture comprises at least 90% EPA and DHA by weight of thefatty acid oil mixture, of which at least 95% is DHA.

Supplement

The present disclosure further provides a food supplement or anutritional supplement comprising a fatty acid oil mixture, wherein thefatty acid oil mixture comprises less than 75% EPA and DHA by weight ofthe fatty acid oil mixture. In some embodiments, for example, the fattyacid oil mixture comprises less than 70% EPA and DHA by weight of thefatty acid oil mixture, such as less than 65%, less than 60%, less than55%, less than 50%, less than 45%, less than 40%, or even less than 35%by weight of the fatty acid oil mixture.

In some embodiments, the fatty acid oil mixture comprises from about 25%to about 75% EPA and DHA by weight of the fatty acid oil mixture, suchas from about 30% to about 75%, from about 30% to about 70%, from about30% to about 65%, from about 30% to about 55%, from about 30% to about50%, from about 30% to about 45%, from about 30% to about 40%, andfurther for example, from about 30% to about 35% EPA and DHA, by weightof the fatty acid oil mixture.

Surfactant/Preconcentrate

The present disclosure provides for a preconcentrate composition,wherein the term “preconcentrate” refers to a composition comprising atleast a fatty acid oil mixture and at least one surfactant. In someembodiments, for example, the preconcentrate comprises a fatty acid oilmixture in a form chosen from ethyl ester and triglyceride, at least onefree fatty acid, and at least one surfactant. In other embodiments, thepreconcentrate comprises a fatty acid oil mixture in free acid form andat least one surfactant. In still other embodiments, the preconcentratecomprises a fatty acid oil mixture in a form chosen from ethyl ester andtriglyceride and at least one surfactant.

A surfactant may, for example, lower the surface tension of a liquid orthe surface tension between two liquids. For example, surfactantsaccording to the present disclosure may lower the surface tensionbetween the fatty acid oil mixture and an aqueous solution.

Chemically speaking, surfactants are molecules with at least onehydrophilic part and at least one hydrophobic (i.e., lipophilic) part.Surfactant properties may be reflected in the hydrophilic-lipophilicbalance (HLB) value of the surfactant, wherein the HLB value is ameasure of the degree of hydrophilic versus lipophilic properties of asurfactant. The HLB value normally ranges from 0 to 20, where a HLBvalue of 0 represents high hydrophilic character, and a HLB of 20represents high lipophilic character. Surfactants are often used incombination with other surfactants, wherein the HLB values are additive.The HLB value of surfactant mixtures may be calculated as follows:

HLB _(A)(fraction of surfactant A)+HLB _(B)(fraction of surfactantB)=HLB _(A+B mixture)

Surfactants are generally classified as ionic surfactants, e.g., anionicor cationic surfactants, and nonionic surfactants. If the surfactantcontains two oppositely charged groups, the surfactant is named azwitterionic surfactant. Other types of surfactants include, forexample, phospholipids.

In at least one embodiment of the present disclosure, the compositioncomprises at least one surfactant chosen from nonionic, anionic,cationic, and zwitterionic surfactants.

Non-limiting examples of nonionic surfactants suitable for the presentdisclosure are mentioned below.

Pluronic® surfactants are nonionic copolymers composed of a centralhydrophobic polymer (polyoxypropylene(poly(propylene oxide))) with ahydrophilic polymer (polyoxyethylene(poly(ethylene oxide))) on eachside. Various commercially-available Pluronic® products are listed inTable 1.

TABLE 1 Examples of Pluronic ® surfactants. Average Molecular TypeWeight (D) HLB Value Pluronic ® L-31 Non-ionic 1100 1.0-7.0 Pluronic ®L-35 Non-ionic 1900 18.0-23.0 Pluronic ® L-61 Non-ionic 2000 1.0-7.0Pluronic ® L-81 Non-ionic 2800 1.0-7.0 Pluronic ® L-64 Non-ionic 290012.0-18.0 Pluronic ® L-121 Non-ionic 4400 1.0-7.0 Pluronic ® P-123Non-ionic 5800 7-9 Pluronic ® F-68 Non-ionic 8400 >24 Pluronic ® F-108Non-ionic 14600 >24

Brij® are nonionic surfactants comprising polyethylene ethers. Variouscommercially-available Brij® products are listed in Table 2.

TABLE 2 Examples of Brij ® surfactants. HLB Type Compound Value Brij ®30 Non-ionic Polyoxyethylene(4) lauryl ether 9.7 Brij ® 35 Non-ionicpolyoxyethylene (23) lauryl ether 16.9 Brij ® 52 Non-ionicPolyoxyethylene (2) cetyl ether 5.3 Brij ® 56 Non-ionic Polyoxyethylene(10) cetyl ether 12.9 Brij ® 58 Non-ionic Polyoxyethylene (20) cetylether 15.7 Brij ® 72 Non-ionic polyoxyethylene (2) stearyl ether 4.9Brij ® 76 Non-ionic polyoxyethylene (10) stearyl ether 12.4 Brij ® 78Non-ionic polyoxyethylene (20) stearyl ether 15.3 Brij ® 92V Non-ionicPolyoxyethylene (2) oleyl ether 4.9 Brij ® 93 Non-ionic Polyoxyethylene(2) oleyl ether 4 Brij ® 96V Non-ionic polyethylene glycol oleyl ether12.4 Brij ® 97 Non-ionic Polyoxyethylene (10) oleyl ether 12 Brij ® 98Non-ionic Polyoxyethylene (20) oleyl ether 15.3 Brij ® 700 Non-ionicpolyoxyethylene (100) stearyl ether 18

Span® are nonionic surfactants comprising sorbitan esters. Span® isavailable from different sources including Aldrich. Variouscommercially-available Span® products are listed in Table 3.

TABLE 3 Examples of Span ® surfactants. Type Compound HLB Value Span ®20 Non-ionic sorbitan monolaurate 8.6 Span ® 40 Non-ionic sorbitanmonopalmitate 6.7 Span ® 60 Non-ionic sorbitan monostearate 4.7 Span ®65 Non-ionic sorbitan tristearate 2.1 Span ® 80 Non-ionic sorbitanmonooleate 4.3 Span ® 85 Non-ionic Sorbitan trioleate 1.8

Tween® (polysorbates) are nonionic surfactants comprisingpolyoxyethylene sorbitan esters. Various commercially-available Tween®products are listed in Table 4.

TABLE 4 Examples of Tween ® surfactants. HLB Type Compound Value Tween ®Non-ionic polyoxyethylene (20) 16.0 20 sorbitan monolaurate Tween ®Non-ionic polyoxyethylene (20) 15.6 40 sorbitan monopalmitate Tween ®Non-ionic polyoxyethylene sorbitan 14.9 60 monostearate Tween ®Non-ionic polyoxyethylene sorbitan 10.5 65 tristearate Tween ® Non-ionicpolyoxyethylene(20)sorbitan 15.0 80 monooleate Tween ® Non-ionicpolyoxyethylene sorbane 11.0 85 trioleate

Myrj® are nonionic surfactants comprising polyoxyethylene fatty acidesters. Various commercially-available Myrj® products are listed inTable 5.

TABLE 5 Examples of Myrj ® surfactants. HLB Type Compound Value Myrj ®45 Non-ionic polyoxyethylene 11.1 monostearate Myrj ® 49 Non-ionicpolyoxyethylene 15.0 monostearate Myrj ® 52 Non-ionic polyoxyethylene16.9 monostearate Myrj ® 53 Non-ionic polyoxyethylene 17.9 monostearate

Cremophor® are nonionic surfactants. Various commercially-availableCremophor® products are listed in Table 6.

TABLE 6 Examples of Cremophor ® surfactants. HLB Type Compound ValueCremophor ® REL Non-ionic polyoxyethylated castor oil  2-14 Cremophor ®RH40 Non-ionic hydrogenated 14-16 polyoxyethylated castor oilCremophor ® RH60 Non-ionic hydrogenated 15-17 polyoxyethylated castoroil Cremophor ® RO Non-ionic hydrogenated 16.1 polyoxyethylated castoroil

According to the present disclosure, other exemplary nonionicsurfactants include, but are not limited to, diacetyl monoglycerides,diethylene glycol monopalmitostearate, ethylene glycolmonopalmitostearate, glyceryl behenate, glyceryl distearate, glycerylmonolinoleate, glyceryl mono-oleate, glyceryl monostearate, macrogolcetostearyl ether such as cetomacrogol 1000 and polyoxy 20 cetostearylether, macrogol 15 hydroxystearate, macrogol lauril ethers such aslaureth 4 and lauromacrogol 400, macrogol monomethyl ethers, macrogololeyl ethers such as polyoxyl 10 oleyl ether, macrogol stearates such aspolyoxyl 40 stearate, menfegol, mono and diglycerides, nonoxinols suchas nonoxinol-9, nonoxinol-10 and nonoxinol-11, octoxinols such asoctoxinol 9 and oxtoxinol 10, polyoxamers such as polyoxalene,polyoxamer 188, polyoxamer 407, polyoxyl castor oil such as polyoxyl 35castor oil, polyoxyl hydrogenated castor oil such as polyoxyl 40hydrogenated castor oil, propylene glycol diacetate, propylene glycollaurates such as propylene glycol dilaurate and propylene glycolmonolaurate. Further examples include propylene glycolmonopalmitostearate, quillaia, sorbitan esters, and sucrose esters.

Anionic surfactants suitable for the present disclosure include, forexample, salts of perfluorocarboxylic acids and perfluorosulphonic acid,alkyl sulphate salts such as sodium dodecyl sulphate and ammonium laurylsulphate, sulphate ethers such as sodium lauryl ether sulphate, andalkyl benzene sulphonate salts.

Cationic surfactants suitable for the present disclosure include, forexample, quaternary ammonium compounds such as benzalkonium chloride,cetylpyridinium chlorides, benzethonium chlorides, and cetyltrimethylammonium bromides or other trimethylalkylammonium salts.

Zwitterionic surfactants include, but are limited to, for exampledodecyl betaines, coco amphoglycinates and cocamidopropyl betaines.

In some embodiments of the present disclosure, the surfactant maycomprise a phospholipid, derivative thereof, or analogue thereof. Suchsurfactants may, for example, be chosen from natural, synthetic, andsemisynthetic phospholipids, derivatives thereof, and analogues thereof.Exemplary phospholipids surfactants include phosphatidylcholines withsaturated, unsaturated and/or polyunsaturated lipids such asdioleoylphosphatidylcholine, dipentadecanoylphosphatidylcholine,dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine,dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine,di-eicopentaenoyl(EPA)choline, didocosahexaenoyl(DHA)choline,phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserinesand phosphatidylinositols. Other exemplary phospholipid surfactantsinclude soybean lecithin, egg lecithin, diolelyl phosphatidylcholine,distearoyl phosphatidyl glycerol, PEG-ylated phospholipids, anddimyristoyl phosphatidylcholine.

Phospholipids may be “natural” or from a marine origin chosen from, e.g.phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine andphosphatidylinositol. The fatty acid moiety may be chosen from 14:0,16:0, 16: 1n-7, 18:0, 18:1n-9, 18:1n-7, 18:2n-6, 18:3n-3, 18:4n-3,20:4n-6, 20:5n-3, 22:5n-3 and 22:6n-3, or any combinations thereof. Inone embodiment, the fatty acid moiety is chosen from palmitic acid, EPAand DHA.

Other exemplary surfactants suitable for the present disclosure arelisted in Table 7.

TABLE 7 Other surfactants Surfactant Type HBL Value Ethylene glycoldistearate Nonionic 1.5 Glyceryl monostearate Nonionic 3.3 Propyleneglycol monostearate Nonionic 3.4 Glyceryl monostearate Nonionic 3.8Diethylene glycol monolaurate Nonionic 6.1 Acacia Anionic 8.0Cetrimonium bromide Cationic 23.3 Cetylpyridinium chloride Cationic 26.0Polyoxamer 188 Nonionic 29.0 Sodium lauryl sulphate Anionic 40

In some embodiments of the present disclosure, the at least onesurfactant does not comprise Labrasol, Cremophor RH40, or thecombination of Cremophor and Tween-80.

In some embodiments, the at least one surfactant has ahydrophilic-lipophilic balance (HLB) of less than about 10, such as lessthan about 9, or less than about 8.

The weight ratio of EPA and DHA to the at least one surfactant may rangedepending on the choice of surfactant(s), the EPA to DHA ratio, and theoverall formulation. In some embodiments of the present disclosure, theweight ratio of EPA and DHA:surfactant ranges from about 10:5 to about10:0.001, from about 10:4 to about 10:0.005, from about 10:3 to about10:0.01, from about 10:2 to about 0.015, from about 10:2 to about10:0.02, or from about 10:15 to about 10:0.03.

Co-Surfactant

In some embodiments, the preconcentrates of the present disclosurefurther comprise at least one co-surfactant. As used herein the term“co-surfactant” means a substance added to, e.g., the preconcentrate incombination with the at least one surfactant to affect, e.g., increaseor enhance, emulsification and/or stability of the preconcentrate, forexample to aid in forming an emulsion. In some embodiments, the at leastone co-surfactant is hydrophilic.

Examples of co-surfactants suitable for the present disclosure include,but are not limited to, short chain alcohols comprising from 1 to 6carbons (e.g., ethanol), benzyl alcohol, alkane diols and triols (e.g.,propylene glycol, glycerol, polyethylene glycols such as PEG and PEG400), glycol ethers such as tetraglycol and glycofurol (e.g.,tetrahydrofurfuryl PEG ether), pyrrolidine derivatives such asN-methylpyrrolidone (e.g., Pharmasolve®) and 2-pyrrolidone (e.g.,Soluphor® P), and bile salts, for example sodium deoxycholate. Furtherexamples include ethyl oleate.

In some embodiments, the at least one co-surfactant comprises from about1% to about 10%, by weight relative to the weight of the preconcentrate.

Solvent

In some embodiments, the compositions and/or preconcentrates furthercomprise at least one solvent. Hydrophilic solvents suitable for thepresent disclosure include, but are not limited to, alcohols, includingwater-miscible alcohols, such as absolute ethanol and/or glycerol, andglycols, for example glycols obtainable from an oxide such as ethyleneoxide, such as 1,2-propylene glycol. Other non-limiting examples includepolyols, such as polyalkylene glycol, e.g., poly(C₂₋₃)alkylene glycolsuch as polyethylene glycol.

In some embodiments of the present disclosure, the preconcentratecomprises at least one substance that acts both as a co-surfactant and asolvent, for example an alcohol such as ethanol. In other embodiments,the preconcentrate comprises at least one co-surfactant and at least onesolvent that are different substances. For example, in some embodimentsthe preconcentrate comprises ethanol as the co-surfactant and glycerolas the solvent.

Superdisintegrant

In some embodiments of the present disclosure, the compositions and/orpreconcentrates may comprise at least one superdistintegrant.Superdisintegrants may, for example, improve disintegrant efficiencyresulting in decreased use levels in comparison to traditionaldisintegrants. Examples of superdisintegrants include, but are notlimited to, crosscarmelose (a crosslinked cellulose), crospovidone (acrosslinked polymer), sodium starch glycolate (a crosslinked starch),and soy polysaccharides. Commercial examples of superdisintegrantsinclude Kollidon® (BASF), Polyplasdone® XL (ISP), and Ac-Di-Sol (FMCBioPolymer).

The compositions and/or preconcentrates may comprise from about 1% toabout 25% of at least one superdisintegrant by weight, such as fromabout 1% to about 20% by weight, or from about 1% to about 15% by weightof the composition and/or preconcentrate. In some embodiments, thecompositions and/or preconcentrates comprising at least onesuperdisintegrant are in a tablet form.

In some embodiments, the weight ratio of fatty acid oilmixture:surfactant of the preconcentrate ranges from about 1:1 to about10:1, from about 1.1 to about 8:1, from 1:1 to about 7:1, from 1:1 toabout 6:1, from 1:1 to about 5:1, from 1:1 to about 4:1, from 1:1 toabout 3:1, or from 1:1 to about 2:1.

In some embodiments, the at least one surfactant comprises from about 5%to about 55%, by weight relative to the total weight of thepreconcentrate. For example, in some embodiments, the at least onesurfactant comprises from about 5% to about 35%, from about 10% to about35%, from about 15% to about 35%, from about 15% to about 30%, or fromabout 20% to about 30%, by weight, relative to the total weight of thepreconcentrate.

SNEDDS/SMEDDS/SEDDS

The preconcentrate of the present disclosure may be in a form of aself-nanoemulsifying drug delivery system (SNEDDS), aself-microemulsifying drug delivery system (SMEDDS), or a selfemulsifying drug delivery system (SEDDS), wherein the preconcentrateforms an emulsion in an aqueous solution.

Without being bound by theory, it is believed that the preconcentrateforms a SNEDDS, SMEDDS, and/or SEDDS upon contact with gastric and/orintestinal media in the body, wherein the preconcentrate forms anemulsion comprising micelle particles. The emulsion may, for example,provide for increased or improved stability of the fatty acids foruptake in the body and/or provide increased or improved surface area forabsorption. SNEDDS/SMEDDS/SEDDS may thus provide for enhanced orimproved hydrolysis, solubility, bioavailability, absorption, or anycombinations thereof of fatty acids in vivo.

Generally, known SNEDDS/SMEDDS/SEDDS formulations comprise ˜10 mg of adrug and ˜500 mg of surfactants/co-surfactants. The SNEDDS/SMEDDS/SEDDSpresently disclosed may have the opposite relationship, i.e., the amountof fatty acid oil mixture comprising the active pharmaceuticalingredient (API) is greater than the amount of surfactant.

The SNEDDS/SMEDDS/SEDDS presently disclosed may comprise a particle size(i.e., particle diameter) ranging from about 5 nm to about 10 μm. Forexample, in some embodiments, the particle size ranges from about 5 nmto about 1 μm, such as from about 50 nm to about 750 nm, from about 100nm to about 500 nm, or from about 150 nm to about 350 nm.

Excipients

The compositions, preconcentrates, and/or SNEDDS/SMEDDS/SEDDS presentlydisclosed may further comprise at least one non-active pharmaceuticalingredient, e.g., excipient. Non-active ingredients may solubilize,suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color,flavor, and/or fashion active ingredients into an applicable andefficacious preparation, such that it may be safe, convenient, and/orotherwise acceptable for use. The at least one non-active ingredient maybe chosen from colloidal silicon dioxide, crospovidone, lactosemonohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol,povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titaniumdioxide, and xanthum gum.

The compositions, preconcentrates, and/or SNEDDS/SMEDDS/SEDDS presentlydisclosed may further comprise at least one antioxidant. Examples ofantioxidants suitable for the present disclosure include, but are notlimited to, α-tocopherol (vitamin E), calcium disodium EDTA, alphatocoferyl acetates, butylhydroxytoluenes (BHT), and butylhydroxyanisoles(BHA).

Forms

The compositions and/or preconcentrates presently disclosed may beadministered, e.g., in capsule, tablet, sachet, or any other formsuitable for drug delivery. The dosage form can be of any shape suitablefor oral administration, such as spherical, oval, ellipsoidal,cube-shaped, regular, and/or irregular shaped. The dosage forms can beprepared according to processes known in the art and can include one ormore additional pharmaceutically-acceptable excipients as discussedabove.

In some embodiments of the present disclosure, the compositions and/orpreconcentrates are in a capsule or a tablet form. The capsulewall-forming material may comprise, for example, gelatin orpolysaccharides other than alginate. In at least one embodiment, thecapsule is a gelatin capsule. The capsules may be hard capsules or softcapsules.

When the dosage form is in the form of tablets, the tablets may be, forexample, disintegrating tablets, fast dissolving tablets, effervescenttablets, fast melt tablets, and/or mini-tablets. Tablet formulations aredescribed, for example, in patent publication WO 2006/000229. In someembodiments of the present disclosure, the tablets comprise Neusilin(e.g., magnesium aluminometasilicate).

The capsules and/or tablets of the present disclosure may comprise atleast one coating. Such coatings can delay the release of the capsule ortablet (e.g., release of EPA and/or DHA) for a predetermined period. Forexample, the at least one coating may allow the dosage form to passthrough the stomach without being subjected to stomach acid or digestivejuices to provide for delayed release of EPA and/or DHA outside of thestomach. In some embodiments, the capsules and/or tablets release lessthan 30% of the total EPA and/or DHA in the stomach, such as less than25%, less than 20%, less than 15%, or less than 10%.

In some embodiments, the at least one coating is chosen from entericcoatings, sub-layers, top-layers, and combinations thereof. The term“sub-layer” as used herein means a coating layer located between thecapsule wall material (e.g., gelatin wall) or the tablet surface and anenteric coating. The term “top-layer” as used herein means a coatinglayer over an enteric coating covering the capsule wall material or thetablet surface. The chemical composition of sub-layers and top-layersmay vary depending upon the overall composition of the capsule ortablet. Typical materials for the sub-layers and top-layers presentlydisclosed include film-forming agents such as polysaccharides, forexample hydroxypropyl methyl cellulose.

In embodiments of the present disclosure, the capsules and/or tabletscomprise at least one enteric coating. In some embodiments, the capsulesand/or tablets comprise at least one enteric coating and at least onetop-layer over the at least one enteric coating. In other embodiments,the capsules and/or tablets comprise at least one enteric coating and atleast one sub-layer between the capsule wall or the tablet surface andthe at least one enteric coating. In still other embodiments, thecapsules and/or tablets comprise at least one enteric coating, at leastone sub-layer between the capsule wall or the tablet surface, and atleast one top-layer over the at least one enteric coating. In someembodiments, at least one of the sub-layer(s) and/or top-layer(s)comprises hydroxypropyl methyl cellulose.

In some embodiments, the at least one sub-layer comprises a sealant.Suitable sealants may comprise, for example, permeable or soluble agentssuch as hydroxypropyl methyl cellulose, hydroxypropyl cellulose,hydroxypropyl ethylcellulose, and xanthan gum. Other agents can be addedto improve the processability of the sealant or barrier layer. Suchagents include talc, colloidal silica, polyvinyl alcohol, titaniumdioxide, micronized silica, fumed silica, glycerol monostearate,magnesium trisilicate and magnesium stearate, or a mixture thereof. Thesealant or barrier layer can be applied from solution (e.g., aqueous) orsuspension using any known means, such as a fluidized bed coater (e.g.,Wurster coating) or pan coating system. Suitable sealants or barriersinclude, for example, Opadry® products such as Opadry® II available fromColorcon.

In some embodiments, the at least one coating is pH-independent.Coatings with pH-independent profiles generally erode or dissolve awayafter a predetermined period, and the period is generally directlyproportional to the thickness of the coating. In other embodiments, theat least one coating is pH-dependent. Coatings with pH-dependentprofiles can generally maintain their integrity while in the acid pH ofthe stomach, but erode or dissolve upon entering the more basic upperintestine. In some embodiments, the at least one coating is insoluble ata pH below about 5 and soluble at a pH above about 6.

Examples of coating materials suitable for the present disclosureinclude, but are not limited to, gelatin, film-forming agents, polymers,and copolymers. Examples of polymers and copolymers include, but are notlimited to, acrylate-based polymers and copolymers (e.g., methacrylicacid, copolymers between methacrylic acid and methyl methacrylate,copolymers between methacrylic acid and methyl acrylate, copolymersbetween methacrylic acid and ethyl methacrylate, and copolymers betweenmethacrylic acid and ethyl acrylate) and polysaccharide and/orcellulose-based polymers and copolymers (e.g., cellulose acetatephthalate, hydroxypropyl methyl cellulose phthalate, and hydroxypropylmethyl cellulose acetate succinate). Others polymers include, forexample, polyvinyl acetate phthalate. Additional materials suitable forthe at least one coating include pharmaceutically acceptable acidiccompounds that may not dissolve at the low pH in the stomach, but maydissolve at higher pH in the lower part of the gastrointestinal system.

Commerically-available examples of polymers suitable for the presentdisclosure include EUDRAGIT® products from Evonik. EUDRAGIT® polymersare polymeric lacquer substances based on acrylates and/ormethacrylates, and may be pH-independent or pH-dependent.

For example, EUDRAGIT® RL and EUDRAGIT® RS are acrylic resins comprisingcopolymers of acrylic and methacrylic acid esters with a low content ofquaternary ammonium groups. The ammonium groups are present as salts andgive rise to permeability of the lacquer films. EUDRAGIT® RL andEUDRAGIT® RS are freely permeable (RL) and slightly permeable (RS),respectively, independent of pH. The polymers swell in water anddigestive juices, in a pH-independent manner. In the swollen state, theyare permeable to water and to dissolved active compounds. Specificexamples include EUDRAGIT® RL 30D, EUDRAGIT® RL PO, EUDRAGIT® RL 100,EUDRAGIT® RL 12,5, EUDRAGIT® RS 30D, EUDRAGIT® RS PO, EUDRAGIT® RS 100,and EUDRAGIT® RS 12,5. Additional examples of pH-independent polymersinclude EUDRAGIT® E 100, EUDRAGIT® E 12,5, and EUDRAGIT® E PO. In atleast one embodiment of the present disclosure, the at least one coatingcomprises EUDRAGIT® RS 30D.

Further, for example, EUDRAGIT® L and EUDRAGIT® S are anionic polymerssynthesized from methacrylic acid and methacrylic acid methyl ester.They are insoluble in acids and pure water, and become soluble inneutral to weakly alkaline conditions. The permeability of EUDRAGIT® Land EUDRAGIT S is pH dependent. Above pH 5.0, the polymers becomeincreasingly permeable. Specific examples include EUDRAGIT® L100-55,EUDRAGIT® L30D-55, EUDRAGIT® L100, EUDRAGIT® L100 12,5, EUDRAGIT® S100,EUDRAGIT® S12,5, and EUDRAGIT® FS 30D. Additional examples ofpH-dependent polymers include EUDRAGIT® E100, EUDRAGIT® E 12,5, andEUDRAGIT® PO. In at least one embodiment of the present disclosure, theat least one coating comprises EUDRAGIT® L100-55.

The at least one coating may comprise at least one plasticizer.Plasticizers may, for example to improve the mechanical properties ofpH-sensitive materials of the at least one coating. Suitableplasticizers include, but are not limited to, triethyl citrate,triacetin, polyethylene glycols, propylene glycol, phthalates, sorbitoland glycerin. The amount of plasticizer may vary depending upon thechemical composition of the at least one coating and the chemicalcomposition and size of the capsule or tablet. In some embodiments, forexample, the amount of plasticizer ranges from about 10% to about 60% byweight of the at least one coating.

The amount of coating material or thickness of the at least one coatingmay vary depending upon the chemical compositions and number ofdifferent coating layers, and chemical composition, size, and shape ofthe capsule or the tablet. Generally speaking, the coating should besufficient thick to prevent substantial release of EPA and/or DHA in thestomach, but also not contribute significantly to the capsule or tabletsize. In some embodiments of the present disclosure, the thickness ofthe at least one coating ranges from about 10 microns to about 2 mm,such as from about 20 microns to about 1 mm. In some embodiments, the atleast one coating comprises from about 1% to about 50% of the drycapsule wall-forming material (e.g., gelatin).

The capsules according to the present disclosure may be manufactured inlow oxygen conditions to inhibit oxidation during the manufacturingprocess. The capsules may be prepared, for example, by directencapsulation using standard methods known in the art. Examples of suchmethods include, but are not limited to, simple coacervation methods(see, e.g., ES 2009346, EP 0052510, and EP 0346879), complexcoacervation methods (see, e.g., GB 1393805), double emulsion methods(see, e.g., U.S. Pat. No. 4,652,441), simple emulsion methods (see,e.g., U.S. Pat. No. 5,445,832), and solvent evaporation methods (see,e.g., GB 2209937). Those methods may, for example, provide forcontinuous processing and flexibility of batch size. The presentdisclosure further provides for coating pre-prepared capsules (e.g.,gelatin capsules comprising a fatty acid oil mixture). The coating ofpre-prepared capsules may be performed, for example, by spraying such asusing spray drying techniques or spraying into a coating pan comprisingpreformed capsules, or by dipping capsules into coating solutions.

In some embodiments of the present disclosure, the capsule fill contentranges from about 0.400 g to about 1.600 g. For example, in someembodiments, the capsule fill content ranges from about 0.400 g to about1.300 g, from about 0.600 g to about 1.200 g, from about 0.600 g toabout 0.800 g, from about 0.800 g to about 1.000, from about 1.000 g toabout 1.200 g, or any amount in between. For example, in someembodiments the capsule fill content is about 0.600 g, about 0.800 g,about 1.000 g, or about 1.200 g.

In some embodiments of the present disclosure, the compositions and/orpreconcentrates comprise from about 300 mg to about 400 mg of DHA, suchas about 375 mg. In some embodiment, the compositions and/orpreconcentrates comprise from about 400 mg to about 500 mg of EPA, suchas about 465 mg. In one embodiment, for example, the compositions and/orpreconcentrates comprise about 375 mg of DHA and about 465 mg of EPA.

Methods or Uses

The present disclosure further encompasses methods of treating and/orregulating at least one health problem in a subject in need thereof. Thecompositions and preconcentrates presently disclosed may beadministered, e.g., in capsule, tablet or any other suitable form fordrug delivery, to a subject for therapeutic treatment and/or regulationof at least one health problem including, for example, irregular plasmalipid levels, cardiovascular functions, immune functions, visualfunctions, insulin action, neuronal development, heart failure, and postmyocardial infarction. In some embodiments, the at least one healthproblem is chosen from mixed dyslipidemia, dyslipidemia,hypertriglyceridemia, hypercholesterolemia, heart failure, andpost-myocardial infarction.

In one embodiment, the present disclosure provides for a method oftreating at least one health problem in a subject in need thereof,comprising administering to the subject a pharmaceutical composition ina gelatin capsule or a tablet form comprising apharmaceutically-effective amount of a fatty acid oil mixture comprisingat least 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),by weight of the fatty acid oil mixture, wherein the EPA and DHA are ina form chosen from ethyl ester and triglyceride; and at least one freefatty acid; wherein the gelatin or the tablet comprises at least onecoating. In some embodiments, the method treats at least one of elevatedtriglyceride levels, non-HDL cholesterol levels, LDL cholesterol levelsand/or VLDL cholesterol levels. For example, the method may reducetriglyceride levels from about 30% to about 80%, such as from about 40%to about 70%, from about 40% to about 60%, or from about 30% to about50%, in a subject with elevated triglyceride levels.

In another embodiment, the present disclosure provides for a method ofregulating at least one health problem in a subject in need thereof,comprising administering to the subject administering to the subject asupplement composition in a gelatin capsule or a tablet form comprising:a fatty acid oil mixture comprising from about 25% to about 75%eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight ofthe fatty acid oil mixture, wherein the EPA and DHA are in a form chosenfrom ethyl ester and triglyceride; and at least one free fatty acid;wherein the gelatin capsule or the tablet comprises at least onecoating, and wherein the at least one health problem is chosen fromirregular plasma lipid levels, cardiovascular functions, immunefunctions, visual functions, insulin action, neuronal development, heartfailure, and post myocardial infarction.

The present disclosure further provides for a method for enhancing atleast one parameter chosen from hydrolysis, solubility, bioavailability,absorption, and combinations thereof of EPA and/or DHA. Thebioavailability may be increased, for example, by at least 40%, such asby about 80% or by at least 85%.

In one embodiment, the method for enhancing at least one parameterchosen from hydrolysis, solubility, bioavailability, absorption, andcombinations thereof of EPA and/or DHA comprises: combining a fatty acidoil mixture comprising EPA and DHA in a form chosen from ethyl ester andtriglyceride; and at least one free fatty acid in a gelatin capsule or atablet form, wherein the gelatin capsule or the tablet comprises atleast one coating.

In another embodiment, the method for enhancing at least one parameterchosen from hydrolysis, solubility, bioavailability, absorption, andcombinations thereof of EPA and/or DHA comprises: combining a fatty acidoil mixture comprising EPA and DHA in a form chosen from ethyl ester andtriglyceride; at least one free fatty acid; and at least one surfactantin a gelatin capsule or a tablet form, wherein the gelatin capsule orthe tablet comprises at least one coating.

In another embodiment, the method for enhancing at least one parameterchosen from hydrolysis, solubility, bioavailability, absorption, andcombinations thereof of EPA and/or DHA comprises: combining a fatty acidoil mixture comprising EPA and DHA in free acid form and at least onefree fatty acid in a gelatin capsule or a tablet form, wherein thegelatin capsule or the tablet comprises at least one coating.

In yet another embodiment, the method for enhancing at least oneparameter chosen from hydrolysis, solubility, bioavailability,absorption, and combinations thereof of EPA and/or DHA comprises:combining a fatty acid oil mixture comprising EPA and DHA in a formchosen from ethyl ester and triglyceride and at least one surfactant ina gelatin capsule or a tablet form, wherein the gelatin capsule or thetablet comprises at least one coating.

The preconcentrates presently disclosed can form a self-nanoemulsifyingdrug delivery system (SNEDDS), self-microemulsifying drug deliverysystem (SMEDDS), or self-emulsifying drug delivery system (SEDDS) in anaqueous solution in the methods presently disclosed.

In some embodiments of the present disclosure, the pharmaceutical orsupplement compositions, or pharmaceutical or supplement preconcentratesmay be administered to a subject in need thereof to treat and/orregulate at least one health problem.

In some embodiments, the preconcentrates of the present disclosure forma self-nanoemulsifying drug delivery system (SNEDDS), aself-microemulsifying drug delivery system (SMEDDS), or aself-emulsifying drug delivery system (SEDDS) in an aqueous solution. Insome embodiments, the aqueous solution is gastric media and/orintestinal media.

The total daily dosage of the fatty acid oil mixture may range fromabout 0.600 g to about 6.000 g. For example, in some embodiments, thetotal dosage of the fatty acid oil mixture ranges from about 0.800 g toabout 4.000 g, from about 1.000 g to about 4.000 g, from about 0.5000 gto about 4.000 g, from about 0.250 g to about 2.000 g, from about 0.400g to about 2.000 g, or from about 1.000 g to about 2.000 g. In oneembodiment, the fatty acid oil mixture is chosen from K85EE and AGP 103fatty acid oil compositions. In another embodiment, the fatty acid oilmixture comprises K85FA.

The administration may be oral or any other form of administration thatprovides a dosage of fatty acids, e.g., omega-3 fatty acids, to asubject, such as a human. For example, the compositions andpreconcentrates presently disclosed may be administered as capsulesand/or tablets in from 1 to 10 dosages, such as from 1 to 4 times a day,such as once, twice, three times, or four times per day, and further forexample, once, twice or three times per day.

Formulations

In some embodiments of the present disclosure, the preconcentrate is apharmaceutical preconcentrate in a gelatin capsule or a tablet formcomprising a fatty acid oil mixture comprising at least 75%eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight ofthe fatty acid oil mixture, wherein the EPA and DHA are in a form chosenfrom ethyl ester and triglyceride; at least one free fatty acid; and atleast one surfactant, wherein the gelatin capsule or the tabletcomprises at least one coating.

In one embodiment, the pharmaceutical preconcentrate in a gelatincapsule or a tablet form comprises: a fatty acid oil mixture comprisingat least 95% of EPA ethyl ester, DHA ethyl ester, or mixtures thereof,by weight of the fatty acid oil mixture; at least one free fatty acidchosen from linoleic, α-linolenic acid (ALA), y-linoleic acid (GLA), andoleic acid; and a least one surfactant chosen from polysorbate 20,polysorbate 80, and mixtures thereof, wherein the gelatin capsule or thetablet comprises at least one coating.

In another embodiment, the pharmaceutical preconcentrate in a gelatincapsule or a tablet form comprises: a fatty acid oil mixture comprisingfrom about 80% to about 88% EPA and DHA by weight of the fatty acid oilmixture, wherein the EPA and DHA are in ethyl ester form; at least onefree fatty acid comprising oleic acid; and at least one surfactantchosen from polysorbate 20, polysorbate 80, and mixtures thereof;wherein the at least one surfactant comprises less than 40%, by weightrelative to the weight of the preconcentrate, and wherein the gelatincapsule or the tablet comprises at least one coating.

In another embodiment, the pharmaceutical preconcentrate in a gelatincapsule or a tablet form comprises: a fatty acid oil mixture comprisingfrom about 80% to about 88% EPA and DHA by weight of the fatty acid oilmixture, wherein the EPA and DHA are in ethyl ester form; at least onefree fatty acid comprising linoleic acid; and at least one surfactantchosen from polysorbate 20, polysorbate 80, and mixtures thereof;wherein the at least one surfactant comprises less than 35%, by weightrelative the weight of the preconcentrate, and wherein the gelatincapsule or the tablet comprises at least one coating.

In another embodiment, the pharmaceutical preconcentrate in a gelatincapsule or a tablet form comprises: a fatty acid oil mixture comprisingfrom about 80% to about 88% EPA and DHA by weight of the fatty acid oilmixture, wherein the EPA and DHA are in ethyl ester form; at least onefree fatty acid comprising from about 80% to about 88% EPA and DHA, byweight of the at least one free fatty acid, wherein the EPA and DHA arein free acid form; and at least one surfactant chosen from polysorbate20, polysorbate 80, and mixtures thereof, wherein the gelatin capsule orthe tablet comprises at least one coating. For example, thepharmaceutical preconcentrate may comprise K85EE as the fatty acid oilmixture, K85FA as the at least one free fatty acid, and at least onesurfactant chosen from polysorbate 20, polysorbate 80, and mixturesthereof.

In another embodiment, the pharmaceutical preconcentrate may compriseK85EE as the fatty acid oil mixture, K85FA as the at least one freefatty acid, and at least one surfactant chosen from polysorbate 20 orpolysorbate 80, wherein the [K85EE]:[Tween]:[K85FA] ranges from e.g.about 5:2:0.5 to 5:4:2. In a further embodiment, the ration between[K85EE]:[Tween]:[K85FA] is about [4-5]:[3-4]:[1-1.5].

In another embodiment, minimum of about 5-10% up to maximum of about 50%of fatty acid oil mixture comprising from about 80% to about 88% EPA andDHA by weight of the fatty acid oil mixture, wherein the EPA and DHA arein ethyl ester form, is substituted by a free fatty acid chosen from aK85-FA composition (corresponding to a K85-FA fatty acid profileachieved by hydrolyzing a K85-EE fatty acid ethyl ester composition)EPA, DPA, DHA, and combinations thereof. For example, the EPA-EE andDHA-EE content from 400 mg/g to 840 mg/g of total fatty acid oil mixtureis replaced by 40 to 440 mg/g Free fatty acid chosen from a K85-FAcomposition.

In other embodiments, the preconcentrate in a gelatin capsule or atablet form is a food supplement or nutritional supplementpreconcentrate comprising a fatty acid oil mixture comprising from about25% to about 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid(DHA), by weight of the fatty acid oil mixture, wherein the EPA and DHAare in a form chosen from ethyl ester and triglyceride; at least onefree fatty acid; and at least one surfactant, wherein the gelatincapsule or the tablet comprises at least one coating.

In some embodiments of the present disclosure, the preconcentrate is apharmaceutical preconcentrate in a gelatin capsule or a tablet formcomprising a fatty acid oil mixture comprising at least 75%eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight ofthe fatty acid oil mixture, wherein the EPA and DHA are in free fattyacid form; and at least one surfactant, wherein the gelatin capsule orthe tablet comprises at least one coating.

In one embodiment, for example, the pharmaceutical preconcentrate in agelatin capsule or a tablet form comprises: a fatty acid oil mixturecomprising from about 80% to about 88% EPA and DHA by weight of thefatty acid oil mixture, wherein the EPA and DHA are in free acid form;and at least one surfactant chosen from polysorbate 20, polysorbate 80,and mixtures thereof, wherein the gelatin capsule or the tabletcomprises at least one coating.

In one embodiment, the pharmaceutical preconcentrate in a gelatincapsule or a tablet form comprises: a fatty acid oil mixture comprisingfrom about 80% to about 88% EPA and DHA by weight of the fatty acid oilmixture, wherein the EPA and DHA are in free acid form; and at least onesurfactant chosen from polysorbate 20, polysorbate 80, and mixturesthereof; wherein the at least one surfactant comprises less than 40%, byweight relative to the weight of the preconcentrate, and wherein thegelatin capsule or the tablet comprises at least one coating.

In another embodiment, for example, the pharmaceutical preconcentrate ina gelatin capsule or a tablet form comprises: a fatty acid oil mixturecomprising from about 80% to about 88% EPA and DHA by weight of thefatty acid oil mixture, wherein the EPA and DHA are in free acid form,and oleic acid; and at least one surfactant chosen from polysorbate 20,polysorbate 80, and mixtures thereof; wherein the at least onesurfactant comprises less than 40%, by weight relative to the weight ofthe preconcentrate, and, wherein the gelatin capsule or the tabletcomprises at least one coating.

In another embodiment, the pharmaceutical preconcentrate in a gelatincapsule or a tablet form comprises: a fatty acid oil mixture comprisingfrom about 80% to about 88% EPA and DHA by weight of the fatty acid oilmixture, wherein the EPA and DHA are in free acid form, and α-linoleicacid; and at least one surfactant chosen from polysorbate 20,polysorbate 80, and mixtures thereof; wherein the at least onesurfactant comprises less than 35%, by weight relative the weight of thepreconcentrate, and, wherein the gelatin capsule or the tablet comprisesat least one coating.

In another embodiment, the pharmaceutical pre-concentrate in a gelatincapsule or a tablet form comprises a K85FA fatty acid oil mixture and atleast one surfactant chosen from polysorbate 20 and polysorbate 80,wherein the gelatin capsule or the tablet comprises at least onecoating.

In other embodiments, the preconcentrate is a food supplementpreconcentrate or nutritional supplement preconcentrate in a gelatincapsule or a tablet form comprising a fatty acid oil mixture comprisingfrom about 25% to about 75% eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), by weight of the fatty acid oil mixture,wherein the EPA and DHA are in free acid form; and at least onesurfactant, wherein the gelatin capsule or the tablet comprises at leastone coating.

In some embodiments of the present disclosure, the preconcentrate is apharmaceutical preconcentrate in a gelatin capsule or a tablet formcomprising a fatty acid oil mixture comprising at least 75%eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight ofthe fatty acid oil mixture, wherein the EPA and DHA are in a form chosenfrom ethyl ester and triglyceride; and at least one surfactant, whereinthe gelatin capsule or the tablet comprises at least one coating.

In one embodiment, the pharmaceutical preconcentrate in a gelatincapsule or a tablet form comprises: a fatty acid oil mixture comprisingat least 95% of EPA ethyl ester, DHA ethyl ester, or mixtures thereof,by weight of the fatty acid oil mixture; and a least one surfactantchosen from polysorbate 20, polysorbate 80, and mixtures thereof,wherein the gelatin capsule or the tablet comprises at least onecoating.

In another embodiment, the pharmaceutical preconcentrate in a gelatincapsule or a tablet form comprises: a fatty acid oil mixture comprisingfrom about 80% to about 88% EPA and DHA by weight of the fatty acid oilmixture, wherein the EPA and DHA are in ethyl ester form; and at leastone surfactant chosen from polysorbate 20, polysorbate 80, and mixturesthereof; wherein the at least one surfactant comprises less than 40%, byweight relative to the weight of the preconcentrate, wherein the gelatincapsule or the tablet comprises at least one coating.

In another embodiment, the pharmaceutical preconcentrate in a gelatincapsule or a tablet form comprises: a fatty acid oil mixture comprisingfrom about 80% to about 88% EPA and DHA by weight of the fatty acid oilmixture, wherein the EPA and DHA are in ethyl ester form; and at leastone surfactant chosen from polysorbate 20, polysorbate 80, and mixturesthereof; wherein the at least one surfactant comprises less than 35%, byweight relative the weight of the preconcentrate, wherein the gelatincapsule or the tablet comprises at least one coating.

In some embodiments, for example, the pharmaceutical preconcentrate in agelatin capsule or a tablet form comprises K85EE as the fatty acid oilmixture, and at least one surfactant chosen from polysorbate 20,polysorbate 80, and mixtures thereof, wherein the gelatin capsule or thetablet comprises at least one coating.

In another embodiment, the pharmaceutical preconcentrate in a gelatincapsule or a tablet form comprises a fatty acid oil mixture comprisingfrom about 80% to about 88% EPA and DHA, by weight of the fatty acid oilmixture, wherein the EPA and DHA are in ethyl ester form; at least onesurfactant chosen from polysorbate 80; and at least one co-surfactantcomprising ethanol, and wherein the gelatin capsule or the tabletcomprises at least one coating.

In other embodiments, the preconcentrate is a food supplementpreconcentrate or nutritional supplement preconcentrate in a gelatincapsule or a tablet form comprising a fatty acid oil mixture comprisingfrom about 25% to about 75% EPA and DHA, by weight of the fatty acid oilmixture, wherein the EPA and DHA are in a form chosen from ethyl esterand triglyceride; and at least one surfactant, and, wherein the gelatincapsule or the tablet comprises at least one coating.

The following examples are intended to illustrate the present disclosurewithout, however, being limiting in nature. It is understood that theskilled artisan will envision additional embodiments consistent with thedisclosure provided herein.

EXAMPLES Example 1 Preconcentrates

Different preconcentrates were prepared as described in Table 9. Toprepare the preconcentrates, the components were mixed according to theschemes identified below on a weight to weight basis. Thepreconcentrates were Visually inspected after mixing and again afterbeing stored for 24 hours at room temperature. Under the Preconcentrateheading, a “clear” designation represents a transparent homogenousmixture; an “unclear” designation represents a nonhomogenous mixture,where some turbidity can be observed by visual inspection. The degree ofturbidity was not determined.

All clear preconcentrates were emulsified in gastric media, by addinggastric media (2 ml) to approximately 100 mg of the preconcentrate. Thecomposition of the gastric media is shown in Table 8.

TABLE 8 Composition of Gastric Media. Gastric Media Bile salts, Porcine(mM) 0.08 Lechitin(mM) 0.02 Sodium chloride (mM) 34.2 Pepsin (mg/ml) 0.1pH 1.6 (adjust with 1M HCl) Osmolarity(mOsm/kg) 120

The outcome of the emulsification was recorded approximately 3 hoursafter mixing. A majority of the preconcentrates formed milky emulsionsimmediately after mixing. Emulsions that stayed milky and homogenousafter 3 hours are described as “milky,” under the Emulsion heading.Emulsions that separated or became nonhomogenous or where oil drops wereobserved are described as “separates,” under the Emulsion heading.

Selected emulsions were further characterized by determining theparticle size. Particle size was measured using a Malvern Zetasizer(Malvern Instrument, Worcestershire, UK) with particle size measuringrange of 0.5-6000 nm and Zeta potential of particle range of 3 nm-10 μm.The particle size was measured in triplicate. The K85EE (EE=ethyl ester)fatty acid composition used herein is sold in a gelatin capsule andbranded primarily under the trademarks Lovaza™ or Omacor®.

TABLE 9 Preconcentrates. K85- Tween- Total Particle EE 20 Oleic Acidvol. Pre- Size No. (mg) (mg) (mg) (mg) Ratio conc. Emulsion (nm)  1451.4 234.3 99 784.7 57:29:12 Unclear — —  2 448.8 299.7 53.8 802.355:37:6  Unclear — —  3 451.2 324.7 24.7 800.6 56:40:3  Unclear — — 10400 300 100 800 50:37:12 Clear Milky 271 11 404 298 97 799 50:37:12Clear Milky — 12 500 300 217 1017 49:29:21 Clear Separates — 13 398 30099 797 49:37:12 Clear Milky 257 14 399 252 98 749 53:33:13 ClearSeparates 226 15 400 204 102 706 56:28:14 Clear Separates 199 21 450 198133 781 57:25:17 Clear Separates — 23 549 204 169 922 59:22:18 ClearSeparates — 24 600 200 178 978 61:20:18 Clear Separates — 26 453 214 121788 57:27:15 Clear Separates — 27 456 220 121 797 57:27:15 ClearSeparates — 28 452 228 144 824 54:27:17 Clear Separates — 29 448 230 122800 56:28:15 Clear Separates — 30 452 242 124 818 55:29:15 ClearSeparates — 31 449 251 124 824 54:30:15 Clear Milky — 32 448 260 123 83153:31:14 Clear Separates — 33 452 270 121 843 53:32:14 Clear Separates —34 449 281 123 853 52:32:14 Clear Separates — 35 448 290 121 85952:33:14 Clear Separates — K85- Total Particle EE Tween- Ricinoleic Vol.Pre- Size No. (mg) 20 (mg) Acid (mg) (mg) Ratio conc. Emulsion (nm) 36402 298 98 798 50:37:12 Clear Milky 277 37 402 250 100 752 53:33:13Clear Milky 268 38 400 200 100 700 57:28:14 Unclear — — 39 450 250 100800 56:31:12 Clear Milky — 43 400 110 100 610 65:18:16 Clear Separates —44 500 270 105 875 57:30:12 Clear Separates — 45 505 295 103 90355:32:11 Clear Milky — 46 525 250 143 918 57:27:15 Clear Separates — 47500 252 118 870 57:28:13 Clear Separates — 48 297 293 145 735 40:39:19Clear Separates — 49 500 260 127 887 56:29:14 Clear Separates — 50 499285 106 890 56:32:11 Clear Separates — 51 403 298 193 894 45:33:21 ClearMilky — 52 460 250 90 800 57:31:11 Clear — — K85- Tween- RicinoleicTotal Particle EE 40 acid Vol. Pre- Size No. (mg) (mg) (mg) (mg) Ratioconc. Emulsion (nm) 53 450 255 98 803 56:31:12 Clear Milky 237 55 498220 98 816 61:26:12 Clear Milky 226 56 505 202 106 813 62:24:13 ClearSeparates — 57 500 200 100 800 62:25:12 Clear Separates — 58 552 152 102806 68:18:12 Clear Separates — K85- Tween- Ricinoleic Total Particle EE60 Acid Vol. Pre- Size No. (mg) (mg) (mg) (mg) Ratio conc. Emulsion (nm)70 500 200 100 800 62:25:12 Clear Milky — 71 500 150 100 750 66:20:13Clear Separates — 72 529 180 104 813 65:22:12 Clear Separates — 73 518200 102 820 63:24:12 Clear Separates — K85- Tween- Ricinoleic TotalParticle EE 80 Acid Vol. Pre- Size No. (mg) (mg) (mg) (mg) Ratio conc.Emulsion (nm) 54 450 270 105 825 54:32:12 Clear Separates — K85-Cremophor Ricinoleic Total Particle EE EL Acid Vol. Pre- Size No. (mg)(mg) (mg) (mg) Ratio conc. Emulsion (nm) 40 399.9 300 106.4 806.349:37:13 Unclear — — 41 400 256.9 137 793.9 50:32:17 Unclear — — K85-Ricinoleic Total Particle EE Soritol Acid Vol. Pre- Size No. (mg) (mg)(mg) (mg) Ratio conc. Emulsion (nm) 42 400 211 104 715 55:29:14 Clear/ —— solid when cooled K85- PEG- Ricinoleic Total Particle EE 400 Acid Vol.Pre- Size No. (mg) (mg) (mg) (mg) Ratio conc. Emulsion (nm) 16 399.9310.2 162.6 872.7 45:35:18 Clear Separates — 17 398.3 256.8 157.9 81348:31:19 Clear Separates — 18 402.4 198.7 147.5 748.6 53:26:19 ClearSeparates — K85- Tween- Total Particle EE 20 PEG-400 Vol. Pre- Size No.(mg) (mg) (mg) (mg) Ratio conc. Emulsion (nm) 19 398.2 297.9 214.7 910.843:32:23 Unclear — — 20 403 248.2 145.3 796.5 50:31:18 Unclear — — K85-α-Linoleic Total Particle EE Tween- Acid Vol. Pre- Size No. (mg) 20 (mg)(mg) (mg) Ratio conc. Emulsion (nm) 74 402 300 100 802 50:37:12 ClearMilky — 75 454 249 98 801 56:31:12 Slightly Separates — dense 76 502 204103 809 62:25:12 Slightly Separates — dense K85- Tween- α-Linoleic TotalParticle EE 40 Acid Vol. Pre- Size No. (mg) (mg) (mg) (mg) Ratio conc.Emulsion (nm) 77 403 299 108 810 49:36:13 Clear/ Separates — Precipitate78 456 252 110 818 55:30:13 Clear/ Separates — Precipitate 79 503 217103 823 61:26:12 Clear/ Separates — Precipitate K85- Tween- α-LinoleicTotal Particle EE 60 Acid Vol. Pre- Size No. (mg) (mg) (mg) (mg) Ratioconc. Emulsion (nm) 80 402 313 104 819 49:38:12 Clear Separates — 81 459205 100 764 60:26:13 Clear Separates — 82 498 198 106 802 62:24:13 ClearSeparates — K85- Tween- α-Linoleic Total Particle EE 80 Acid Vol. Pre-Size No. (mg) (mg) (mg) (mg) Ratio conc. Emulsion (nm) 83 407 317 102826 49:38:12 Clear Milky   261.3 84 455 256 110 821 55:31:13 Clear Milky  260.8 85 498 208 102 808 61:25:12 Clear Milky   274.5 K85- Tween-Erucuc Total Particle EE 20 Acid Vol. Pre- Size No. (mg) (mg) (mg) (mg)Ratio conc. Emulsion (nm) 86 401 300 99 800 50:37:12 Clear Semi — Milky87 451 250 105 806 55:31:13 Clear Separates — 88 504 204 102 81062:25:12 Clear Separates — K85- Tween- Erucuc Total Particle EE 40 AcidVol. Pre- Size No. (mg) (mg) (mg) (mg) Ratio conc. Emulsion (nm) 89 401298 102 801 50:37:12 Clear Separates — 90 451 254 99 804 56:31:12 ClearSeparates — 91 504 219 103 826 61:26:12 Clear Separates — K85- Tween-Erucuc Total Particle EE 60 Acid Vol. Pre- Size No. (mg) (mg) (mg) (mg)Ratio conc. Emulsion (nm) 92 401 301 104 806 49:37:12 Clear Separates —93 454 267 101 822 55:32:12 Clear Separates — 94 497 202 100 79962:25:12 Clear Separates — K85- Tween- Erucuc Total Particle EE 60 AcidVol. Pre- Size No. (mg) (mg) (mg) (mg) Ratio conc. Emulsion (nm) 95 406298 100 804 50:37:12 Clear Separates — 96 450 251 102 803 56:31:12 ClearSeparates — 97 502 205 122 829 60:24:14 Clear Separates — α- K85- Tween-Linolenic Total Particle EE 20 acid Vol. Pre- Size No. (mg) (mg) (mg)(mg) Ratio conc. Emulsion (nm) 98 401 308 105 814 49:37:12 Clear Milky,— beginning separation 102  450 264 108 822 54:32:13 Clear Milky, —beginning separation 106  501 200 111 812 61:24:13 Clear Milky, with —separation α- K85- Tween- Linolenic Total Particle EE 40 Acid Vol. Pre-Size No. (mg) (mg) (mg) (mg) Ratio conc. Emulsion (nm) 99 402 302 102806 49:37:12 Clear Milky, — beginning separation 103  452 254 101 80756:31:12 Clear Milky, with — separation 107  502 206 108 816 61:25:13Clear Milky, with — separation α- K85- Tween- Linolenic Total ParticleEE 60 Acid Vol. Pre- Size No. (mg) (mg) (mg) (mg) Ratio conc. Emulsion(nm) 100  403 303 103 809 49:37:12 Clear Milky, — beginning separation104  450 249 102 801 56:31:12 Clear Milky, with — separation 108  506200 100 806 62:24:12 Unclear Milky, — beginning separation α- K85-Tween- Linolenic Total Particle EE 80 Acid Vol. Pre- Size No. (mg) (mg)(mg) (mg) Ratio conc. Emulsion (nm) 101  403 308 106 817 49:37:12 ClearMilky, — beginning separation 105  452 253 102 807 56:31:12 Clear Milky,with — separation 109  507 203 112 822 61:24:13 Clear Milky, with —separation K85- Tween- Total Particle EE 20 KE85-FA Vol. Pre- Size No.(mg) (mg) (mg) (mg) Ratio conc. Emulsion (nm) 110  398.5 300.5 98.6797.6 49:37:12 Clear Milky (<10 min waiting time) 111  448 245.9 110.4804.3 55:30:13 Unclear — — 112  498.3 197.9 106.2 802.4 62:24:13 Unclear— — K85- Tween- Total Particle EE 40 KE85-FA Vol. Pre- Size No. (mg)(mg) (mg) (mg) Ratio conc. Emulsion (nm) 113  405.7 303.7 105.8 815.249:37:12 Clear Milky — (<10 min waiting time) 114  452.8 261.6 101.8816.2 55:32:12 Clear Milky — (<10 min waiting time) 115  499 212.2 114.7825.9 60:25:13 Clear Milky — (<10 min waiting time) K85- Tween- TotalParticle EE 60 KE85-FA Vol. Pre- Size No. (mg) (mg) (mg) (mg) Ratioconc. Emulsion (nm) 116  395 296.2 100 791.2 49:37:12 Clear Milky — (<10min waiting time) 117  450.3 253.1 98.2 801.6 56:31:12 Clear Milky —(<10 min waiting time) 118  500.8 206 105.7 812.5 61:25:13 Clear Milky —(<10 min waiting time) K85- Tween- Total Particle EE 80 KE85-FA Vol.Pre- Size No. (mg) (mg) (mg) (mg) Ratio conc. Emulsion (nm) 119  402308.3 100.8 811.1 49:38:12 Clear Milky, — sticky (<10 min waiting time)120  456.6 260.3 103.5 820.4 55:31:12 Clear Milky, — sticky (<10 minwaiting time) 121  502.3 202.2 104 808.5 62:25:12 Clear Milky, — sticky(<10 min waiting time)

Of the preconcentrates prepared, formulation number 85 facilitated aload of 60% K85EE into the preconcentrate and gave a stable emulsion ingastric media with a particle size determined to be about 275 nm.Attempts to prepare preconcentrates with saturated fatty acids, stearicacid and decanoic acid failed. Although homogenous preconcentrates couldbe obtained by heating, a precipitation of stearic acid or decanoic acidwas observed upon cooling of the preconcentrate to room temperature.

Example 2 Additional Preconcentrates

Additional preconcentrates were prepared to determine an optimizedamount of surfactant with K85EE and K85FA. The preconcentrates describedin Table 10 were prepared as provided in Example 1. The preconcentrateswere visually inspected after mixing and again after being stored for 24hours at room temperature. Under the Preconcentrate heading, a “clear”designation represents a transparent homogenous mixture; a “turbid”designation represents a nonhomogenous mixture, where some turbidity canbe observed by visual inspection. The degree of turbidity was notdetermined.

TABLE 10 Additional Preconcentrates. K85-EE K85FA (mg) (mg)Preconcentrate Tween20 (mg) 107 307 62 Turbid 107 307 76 Turbid 107 307102 Turbid 107 307 200 Clear 107 307 401 Clear 107 307 803 Clear 107 3071608 Clear 26 300 99 Clear 104 300 99 Clear 201 300 99 Clear 316 300 99Clear 400 300 99 Clear 497 300 99 Turbid 618 300 99 Turbid 405 42 101Clear 405 99 101 Clear 405 202 101 Clear 405 299 101 Clear 405 400 101Clear 405 618 101 Clear 405 1000 101 Clear Tween80 (mg) 407 306 57 Clear407 306 80 Clear 407 306 103 Clear 407 306 202 Clear 407 306 401 Clear28 299 101 Clear 57 299 101 Clear 99 299 101 Clear 233 299 101 Clear 316299 101 Clear 414 299 101 Clear 510 299 101 Clear 569 299 101 Clear 627299 101 Clear 688 299 101 Clear 769 299 101 Clear 402 32 106 Clear 402126 106 Clear 402 229 106 Clear 402 326 106 Clear 402 410 106 Clear 402997 106 Clear Tween40 (mg) 111 311 59 Turbid 111 311 70 Clear 111 311 95Clear 111 311 135 Clear 111 311 244 Clear 111 311 798 Clear 111 311 1567Clear 30 309 98 Clear 110 309 98 Clear 208 309 98 Clear 322 309 98 Clear404 309 98 Clear 501 309 98 Turbid 618 309 98 Turbid 408 38 99 Clear 408105 99 Clear 408 210 99 Clear 408 301 99 Clear 408 398 99 Clear 408 61699 Clear 408 1001 99 Clear

Example 3 Compatibility of Preconcentrates with Solvents

The compatibility of solvents and a preconcentrate having a fixed amountof K85EE and Tween-80 were evaluated. The preconcentrates described inTable 11 were prepared as provided in Example 1, but with the additionof the solvent identified below. The preconcentrates were visuallyinspected after mixing and again after being stored for 24 hours at roomtemperature. Under the Preconcentrate heading, a “clear” designationrepresents a transparent homogenous mixture; a “turbid” designationrepresents a non-homogenous mixture, where some turbidity can beobserved by visual inspection. The degree of turbidity was notdetermined.

TABLE 11 Compatibility of Solvent and Preconcentrates. K85-EE Tween-8096% ethanol 96% ethanol (mg) (mg) (mg) (%) Preconcentrate 400 110 10.72.1 Turbid 400 110 18.7 3.5 Turbid 400 110 28.4 5.3 Turbid 400 110 32.15.9 Turbid 400 110 45.7 8.2 Turbid 400 110 53.5 9.5 Turbid 400 110 61.510.8 Turbid 400 110 69.8 12.0 Turbid 400 110 79.9 13.5 Turbid 400 11091.3 15.2 Turbid 400 110 102.5 16.7 Turbid Propylene K85-EE Tween-80Propylene glycol glycol (mg) (mg) (mg) (%) Preconcentrate 400 110 11.12.1 Turbid 400 110 16.7 3.2 Turbid 400 110 23.1 4.3 Turbid 400 110 32.96.1 Turbid 400 110 41.5 7.5 Turbid 400 110 48.6 8.7 Turbid 400 110 59.910.5 Turbid 400 110 72.9 12.5 Turbid 400 110 81.5 13.8 Turbid 400 11093.5 15.5 Turbid 400 110 104.6 17.0 Turbid K85-EE Tween-80 PEG 300 PEG300 (mg) (mg) (mg) (%) Preconcentrate 400 110 13.9 2.7 Turbid 400 11023.7 4.4 Turbid 400 110 35.6 6.5 Turbid 400 110 47.1 8.5 Turbid 400 11055.0 9.7 Turbid 400 110 68.7 11.9 Turbid 400 110 81.8 13.8 Turbid 400110 90.3 15.0 Turbid 400 110 104.0 16.9 Turbid K85-EE Tween-80 Benzylalcohol Benzyl alcohol (mg) (mg) (mg) (%) Preconcentrate 400 110 0 0Clear 400 110 11.4 2.2 Turbid 400 110 18.1 3.4 Turbid 400 110 30.9 5.7Clear 400 110 45.5 8.2 Clear 400 110 55.6 9.8 Clear 400 110 66.7 11.6Clear 400 110 77.4 13.2 Clear 400 110 92.1 15.3 Clear 400 110 99.0 16.3Clear K85-EE Tween-80 Triacetin Triacetin (mg) (mg) (mg) (%)Preconcentrate 400 110 12.3 2.4 Turbid 400 110 24.3 4.5 Turbid 400 11035.8 6.6 Turbid 400 110 45.3 8.2 Turbid 400 110 57.0 10.1 Turbid 400 11068.1 11.8 Turbid 400 110 80.9 13.7 Turbid 400 110 90.0 15.0 Turbid 400110 101.7 16.6 Turbid 1-octadecanol 1-octadecanol K85-EE Tween-80 99%99% (mg) (mg) (mg) (%) Preconcentrate 400 110 8.6 1.7 Precipitate oleylalcohol K85-EE Tween-80 oleyl alcohol 85% 85% (mg) (mg) (mg) (%)Preconcentrate 400 100 13.0 2.5 Turbid 400 100 26.5 4.9 Turbid 400 10037.3 6.8 Turbid 400 100 49.5 8.8 Turbid 400 100 62.6 10.9 Turbid 400 10077.7 13.2 Turbid 400 100 92.2 15.3 Turbid 400 100 105.7 17.2 Turbid1-tetradecanol 1 tetradecanol K85-EE Tween-80 97% 97% (mg) (mg) (mg) (%)Preconcentrate 400 100 1.7 0.3 Turbid 400 100 10.3 2.0 Turbid 400 10022.7 4.3 Turbid 400 100 35.8 6.6 Precipitate K85-EE Tween-80 glycerolglycerol (mg) (mg) (mg) (%) Preconcentrate 400 100 17.7 3.4 Turbid 400100 28.0 5.2 Turbid 400 100 41.7 7.6 Turbid 400 100 52.8 9.4 Turbid 400100 71.2 12.3 Turbid 400 100 85.4 14.3 Turbid 400 100 92.3 15.3 Turbid400 100 105.7 17.2 Turbid K85-EE Tween-80 Oleic acid 90% Oleic acid 90%(mg) (mg) (mg) (%) Preconcentrate 400 100 13.2 2.5 Turbid 400 100 23.94.5 Turbid 400 100 31.5 5.8 Turbid 400 100 41.4 7.5 Turbid 400 100 51.89.2 Turbid 400 100 65.2 11.3 Clear 400 100 79.8 13.5 Clear 400 100 87.214.6 Clear 400 100 102.2 16.7 Clear 1-docosanol K85-EE Tween-801-docosanol 98% 98% (mg) (mg) (mg) (%) Preconcentrate 400 100 9.6 1.8Precipitate

Example 4 Characterization of Preconcentrates and SNEDDS/SMEDDS/SEDDS

Preconcentrates A-L described in Table 12 were prepared as provided inExample 1.

TABLE 12 Preconcentrates A-L. Precon- K85-EE Surfactant Total vol.centrate (mg) (mg) FFA (mg) (mg) Ratio A 5002.7 Tween-20 Oleic Acid10016.4 49:36:13 3705.8 1307.9 B 5004.9 Tween-80 Oleic Acid 10015.149:37:13 3707.9 1302.3 C 5003.2 Tween-20 Ricioleic acid 10013.4 49:36:133702.1 1308.1 D 5003.5 Tween-80 Ricioleic acid 10010 49:36:13 3703.11303.4 E 5000.4 Tween-20 Linoleic acid 10013.1 49:37:13 3707.4 1305.3 F5001 Tween-80 Linoleic acid 10011.3 49:37:13 3706 1304.3 G 5006.4Tween-20 Erucic acid 10008.7 50:36:12 3702.1 1300.2 H 5004.3 Tween-80Erucic acid 10011.6 49:36:13 3704.1 1303.2 I 5002.9 Tween-20 α-Linolenic10013.1 49:36:13 3700.8 acid 1309.4 J 5003.6 Tween-80 α-Linolenic10017.3 49:36:13 3701.6 acid 1312.1 K 5002.9 Tween-20 “Pure” EPA-10013.1 49:36:13 3700.8 FA + DHA-FA in a ratio close to K85-EE 1309.4 L5002.9 Tween-80 “Pure” EPA- 10013.1 49:36:13 3700.8 FA + DHA-FA in aratio close to K85-EE 1309.4

From Table 12 above, all preconcentrates appeared clear and homogenous,except for the formulation with erucic acid. As such, thepreconcentrates can be mixed in any proportion and these mixtures willstill form homogenous and clear preconcentrates.

Preconcentrates A-L were also screened for compatibility with varioussolvents. The outcome of this screening is shown in Table 13 below. To500 mg of preconcentrate, approximately 50 mg of each solvent was added.Preconcentrate A was used for all the solvents. Ethanol was tested inall the preconcentrates. The preconcentrates were visually inspectedafter mixing and again after being stored for 24 hours at roomtemperature. Under the Preconcentrate heading, a “clear” designationrepresents a transparent homogenous mixture; an “unclear” designationrepresents a nonhomogenous mixture, where some turbidity can be observedby visual inspection. The degree of turbidity was not determined.

TABLE 13 Preconcentrate Compatibility. Preconcentrate SolventPreconcentrate A B-L 96% Ethanol Clear Clear Benzyl alcohol Clear NdPropylene glycol Unclear Nd Triacetin Clear Nd PEG 300 Unclear NdGlycerol Unclear Nd 1-octadecanol 99% Clear, but solid Nd 1-docosanol98% Unclear Nd Oleyl alcohol 85% Clear Nd 1-tetradecanol 97% Clear NdNd—Not determined.

Viscosity can be used as a physical characterization parameter.Viscosity measurements were taken for preconcentrates A-L in triplicate.Generally, the viscosity showed greater sensitivity for the type offatty acid than for the type of surfactant. FIG. 1 graphicallyillustrates the viscosity of preconcentrates A-L. Although the viscositymeasurements cannot distinguish between Tween 20 versus Tween 80, theviscosity can be impacted by the free fatty acid.

Preconcentrates A-F, I and J were diluted in gastric and intestinalmedia to form an emulsion (i.e., SNEDDS/SMEDDS/SEDDS). The compositionof the gastric media is shown in Table 14, and the composition of theintestinal media is shown in Table 15.

TABLE 14 Gastric Media Gastric Media Bile salts, Porcine (mM) 0.08Lechitin (mM) 0.02 Sodium chloride (mM) 34.2 Pepsin (mg/ml) 0.1 pH 1.6(adjust with 1M HCl) Osmolarity (mOsm/kg) 120

TABLE 15 Intestinal Media Intestinal Media Bile salts, Porcine Bileextract, Sigma 5 037K0196 (mM) Phospholipids, LIPOID S PC from 1.25LIPOID AG (mM) Trizma maleate, Sigma Aldrich, T 3128 2 (mM) Na⁺ (mM) 150

Particle size was measured using a Malvern Zetasizer (MalvernInstrument, Worcestershire, UK) with particle size measuring range of0.5-6000 nm and Zeta potential of particle range of 3 nm-10 μm. Theparticle size was measured in triplicate.

For the gastric media, the emulsions were prepared by adding 1 ml ofgastric media to 50 mg of the preconcentrate. Table 16 below providesthe particle size measurements for preconcentrates A-F, I and J in thegastric media. The particle size measurements in gastric media are alsographically illustrated in FIG. 2.

TABLE 16 Particle size measurements for preconcentrates A-F, I and J ingastric media. Preconcentrates A B C D E F I J Size (nm) 269.6 152.1216.8 271 271.1 287.1 165 244.3 Standard 29.63 5.141 26.24 15.94 6.20836.71 15.87 13.67 Deviation

For the intestinal media, the emulsions were prepared by adding thegastric media (100 μl) obtained above to intestinal media (900 μl).Table 17 below provides the particle size measurements forpreconcentrates A-F, I and J in the intestinal media. The particle sizemeasurements in intestinal media are also graphically illustrated inFIG. 2.

TABLE 17 Particle size measurements for preconcentrates A-F, I and J inintestinal media. Preconcentrates A B C D E F I J Size (nm) 245.9 2314266.7 332.5 233.9 1891 224.3 1788 Standard Deviation 7.465 2438 35.3826.63 10.48 1936 13.56 930.5

As shown in FIG. 2, intestinal media has a larger impact on the particlesize distribution and particularly, preconcentrates comprising Tween 80.That observation has been visualized in FIGS. 3-18. FIGS. 3-18 show theread out from the Malvern zetasizer for four consecutive measurements onthe same sample of each respective preconcentrate. All thepreconcentrates give near to unimodal particle size distributions ingastric media, whereas only preconcentrates comprising Tween 20 staysunimodal when transferred to intestinal media.

Example 5 Lipolysis and Solubilization

Studies were done to analyze the rate of lipolysis (i.e., hydrolysis)and solubilization for different preconcentrates comprising K85EE anddifferent free fatty acids and surfactants. Specifically, fourexperiments were designed to determine how the amount of surfactantinfluences the rate and extent of lipolysis and solubilization. Thelipolysis was conducted on SMEDDS formulations comprising K85EE.

Materials

-   -   Bile salts: Porcine Bile extract (Sigma); contains glycine and        taurine conjugates of hyodeoxycholic acid and other bile salts.    -   Pancreatic lipase, Porcine pancreas (Sigma); contains many        enzymes, including amylase, trypsin, lipase, ribonuclease and        protease.    -   Lechitin: Phospholipids (LIPOID S PC from LIPOID AG)    -   Trizma maleate (Sigma Aldrich)    -   Tween 20, Molecular Biology Grade (AppliChem Darmstadt), Tween        80 (Fluka)    -   α-Linoleic acid (Sigma 60%), Oleic acid (Aldrich 90%)    -   K85-EE and K85-FA

Preconcentrates A-E were prepared as summarized in Table 18.

TABLE 18 Preconcentrates A-E. Fatty acid oil Preconcentrate mixture Freefatty acid Surfactant A K85EE (400 mg) oleic acid Tween 20 (300 mg) (100mg) B K85EE (400 mg) oleic acid Tween 20 (75 mg) (100 mg) C K85EE (500mg) linoleic acid Tween 80 (200 mg) (100 mg) D K85EE (400 mg) K85FATween 20 (300 mg) (100 mg) E K85EE (400 mg) — Tween 80 (100 mg)

Lipolysis General Procedure

The in vitro dynamic lipolysis model developed by Zangenberg et al.(Zangenberg, N. H. et al., Eur. J. Pharm. Sci. 14, 237-244, 2001;Zangenberg, N. H., et al., Eur. J. Pharm. Sci. 14, 115-122, 2001) wasused with slight modifications. The lipolysis was conducted in athermostated 600 ml jacketed glass vessel in the presence of porcinebile extract, with continuous addition calcium chloride. The lipasesource was porcine pancreatin and the hydrolysis was followed bytitration with sodium hydroxide solution (1.0 N) using a pH stat (pH6.5). The initial composition of the lipolysis media is shown in Table19.

TABLE 19 Initial composition of lipolysis media. Substance InitialConcentration Pancreatic lipase, Porcine pancreas 800 USP units/ml Bilesalts, Porcine Bile extract 5 mM Phospholipids, LIPOID S PC from LIPOIDAG 1.25 mM Trizma maleate 2 mM Na⁺ 150 mM K85-EE 5.58 mg/ml

The final volume in all experiments was 300 ml and the calciumdispensing rate during the experiments was 0.045 mmol/min (0.09 ml/min).In all experiments, the amount of K85-EE added corresponds to 5.58mg/ml.

To determine the course of K85-EE lipolysis by HPLC, crude samples werewithdrawn and acidified with dilute hydrochloric acid. Theconcentrations of EPA-EE, DHA-EE, EPA-FA and DHA-FA were determined byHPLC in triplicate. Experiments were performed with LC AgilentTechnologies 1200 series at a column temperature of 30° C., mobile phase(A) water (0.1% acetic acid) and (B) MeCN (0.1% acetic acid), withgradient: 0 to 8 minutes, from 70% B to 100% B; 8 to 15 minutes, 100% B;16 to 16 minutes: from 100% B to 70% B, 16 to 20 minutes: 70% B. Theflow rate was 0.5 ml/min, UV @ 210 nM, injection volume: 5 μl, and runtime: 20 minutes.

Concentrations of EPA ethyl ester (EPA-EE), DHA ethyl ester (DHA-EE),EPA free acid (EPA-FA), and DHA free acid (DHA-FA) were monitored overtime and the rate of lipolysis calculated as shown in Table 20 forcomparison with Omacor®.

TABLE 20 Lipolysis of EPA and DHA ethyl ester in comparison to Omacor ®.EPA-EE lipolysis DHA-EE lipolysis % lipolysis (μg/ml/min) (μg/ml/min)K85EE at t = 233 min Omacor ® 1.5 2.3 17 A 2.8 4.5 41 B 2.9 3.9 35 C 3.75.0 47 D 3.5 5.0 55 E 3.8 4.3 45

FIGS. 19, 22, 25, 28, 31, and 34 graphically illustrate thedisappearance of EPA-EE and DHA-EE and the appearance of EPA-FA andDHA-FA during lipolysis of each respective sample examined. Samplepoints from 2 minutes to 233 minutes were included in the graphs. Inaddition, linear regression lines have been included.

FIGS. 20, 23, 26, 29, 32, and 35 provide the percent recovery of EPA+DHAat different time-points for each respective sample examined. Data aregiven as the sum of EPA-EE, DHA-EE, EPA-FA, and DHA-FA and given as apercentage of theoretical amount 5580 μg/ml.

FIGS. 21, 24, 27, 30, 33, and 36 graphically illustrate the percentlipolysis at different time points for EPA-EE, DHA-EE and total K85EE.Values are calculated relative to the total amount of EPA-EE and DHA-EEdetermined by HPLC after lipolysis for 2 minutes.

Example 6 Fatty Acid Oil Mixtures of PharmaceuticalCompositions/Preconcentrates

Fatty acid oil mixtures of pharmaceutical compositions orpreconcentrates, wherein the fatty acid oil mixture is a K85-EEcomposition are presented in Table 21.

TABLE 21 Fatty acid oil mixture for pharmaceuticalcompositions/preconcentrates Fatty acid oil mixture: Maximum 1000 mgK85EE fatty acid oil mixture Minimum Value Value EPAEE + DHAEE 800 mg/g880 mg/g EPA EE 430 mg/g 495 mg/g DHA EE 347 mg/g 403 mg/g Total omega-3EE >90% (w/w) EE = ethyl ester

Example 7 Tablet Formulations

Tablets were prepared by immersing the tablet shown in Table 22 in K85EEoil. The mean liquid loading was 160 mg oil/tablet, corresponding toabout 72 v/v %. The tablet can also be prepared without asuperdisintegrant.

TABLE 22 Tablet formulation Tablet composition Example Neusilin US 89%Ac-Di-Sol (croscarmellose sodium) = 10% superdisintegrants Mg-stearate1.0% 

Example 8 Novel K85 Tablet Formulation

A tablet formulation is prepared with the components identified in Table23 by immersing a tablet in a K85EE or AGP oil and an oil in free acidform.

TABLE 23 K85 tablet formulation K85 or AGP oil loading per tabletMinimum Maximum value EPA EE and DHA EE 125 mg 600 mg Free fatty acidoil 2% corresponding 15% corresponding to to about 2.5 mg about 90 mg

Example 9 Preparation of SEDDS and SMEDDS

The preconcentrate can be prepared by mixing a fatty acid oil mixturetogether with at least one surfactant and a free fatty acid.

The preconcentrate can be visually inspected after mixing and againafter being stored at 24 hours at room temperature and clear andtransparent preconcentrate can be obtained.

To the preconcentrate can then an aqueous medium be added to form anoil-in-water emulsion. The dispersion rate for the formation of theoil-in-water emulsion can be very fast, less than one minute.

The microemulsions formed can then be tested regarding hydrolysis, alsocalled lipolysis.

For example, to determine the course of KE85-EE hydrolysis by HPLC,crude samples can be withdrawn and acidified with dilute hydrochloricacid. The concentrations of EPA-ethyl ester, DHA ethyl ester, EPA-freefatty acid and DHA-free fatty acid can then determined by HPLC.

All samples withdrawn from a non-homogenous phase and some variabilityin recovery can be expected, especially at early time points.

TABLE 24 Initial concentrations of components in the hydrolysis medium.Substance Initial concentration Pancreatic lipase, Porcine pancreas,Sigma 800 USP units/ml 095K1149 Bile salts, Porcine Bile extract, Sigma5 mM 037K0196 Phospholipids, LIPOID S PC from LIPOID AG 1.25 mM Trizmamaleate, Sigma Aldrich, T 3128 2 mM Na⁺ 150 mM KE85-EE 5.58 mg/ml

An example HPLC analytical method can include the following parameters:

Use of a LC-MS manufactured by Agilent Technologies and includes a 1200Series LC and a 6140 Quadropole MS running ChemStation 8.04.01 software;

Column: EclipseXDB C18, 2.1×150 mm, 5 μm, Agilent

Column temperature: 25° C.;

Mobile Phase: A: water (0.1% acetic acid), B: MeCN (0.1% acetic acid);

Gradient: 0 to 8 min, from 70% B to 100% B, 8 to 15 minutes: 100% B,from 16 to 16 minutes: from 100% B to 70% B, 16 to 20 minutes: 70% B;

Flow rate: 0.5 ml/min;

UV @ 210 nM;

Injection volume: 25 μl; and

Run time: 20 minutes.

The oil-in-water emulsions can then be further analyzed to determine theparticle size of the oil droplets. The particle size can be determinedwith Malvern Zetasizer (Malvern Instrument, Worcestershire, UK) havingparticle size measuring range of 0.6-6000 nm and Zeta of particle rangeof 3 nm-10 μm.

Table 25 shows the components that can be included in pharmaceuticalcompositions and food supplement compositions according to the presentdisclosure.

TABLE 25 Sample compositions according to the present disclosure. FoodSupplement Pharmaceutical composition composition Fatty Acid Oil K85EE,K85TG or AGP103 Commercial up- Mixture drug substance concentrated oilmixture in EE and/or TG form Surfactant Tween ® 20 or Tween ® 40 Tween ®20 or Tween ® 40 Free Fatty Acid (EPA-FA and DHA-FA), (EPA-FA + DHA-FA),EPA-FA or DHA-FA EPA-FA or DHA-FA Total Oil Mixture 100% by weight 100%by weight 100% by weight

Further for example, K85EE omega-3 fatty acid oil and the free fattyacid chosen from K85FA having a EPA:DHA-FA ratio more or less equal tothe EPA:DHA-EE ratio in K85EE are exemplified in Table 26.

TABLE 26 Additional compositions according to the present disclosure.Total oil mixture Free Fatty Free Fatty content [oil:co- Fatty Acid FreeAcid: Acid: surfactant ratio] in Oil Fatty EPA-FA or EPA and Total oilSMEDDS/SEDDS Mixture: Acid: DHA- DHA mixture mixture Formulations K85EEK85-FA FA in FA form (by weight) 1.) 80-95% 5-20 w % 100 w % 2.) 70-80%20-30% 100 w % 3.) 50-70% 30-50% 100 w % 4.) 50-60% 40-50% 100 w % 5.)60-70% 30-40% 100 w % 6.) 70-80% 20-30% 100 w % 7.) 80-95%  5-20% 100 w% 8.) >80% <20% 100 w % 9.) 70-80% 20-30% 100 w % 10.) 60-70% 30-40% 100w % 11.) 50-60% 40-50% 100 w % 12.) 85-95%  5-15% 100 w % EPA > DHA 13.)80-90% 10-20% 100 w % EPA > DHA 14.) 70-80% 20-30% 100 w % EPA > DHA15.) 60-70% 30-40% 100 w % EPA > DHA

Additionally, the total oil mixtures presented above can be mixed withthe surfactant Tween®20.

Further for example, the K85EE mixed fatty acid composition comprises atleast 90% omega-3 ethyl ester fatty acids, and wherein the mixed fattyacid composition comprises from about 80% to about 88% eicosapentaenoicacid ethyl ester and docosahexaenoic acid ethyl ester, by weight of thefatty acid composition.

A collection of ratios between [oil]:[surfactant]:[free fatty acid](a):b):c)) are illustrated in Table 27. For example, a K85EE or AGP103oil is used together with a surfactant and a co-surfactant in the[K85EE]:[surfactant]:[free fatty acid] ranges from about 4:2:0.5 to4:4:2. Thus, the range for the surfactant may be from 2 to 4 and thefree fatty acid from 0.5 to 2.

It is also included herein that the K85EE oil mixture presented in Table27 above can be replaced by a K85TG oil mixture as well as a commercialomega-3 oil concentrate in ethyl ester and/or triglyceride form.

TABLE 27 SMEDDS formulations with Tween20, K85EE, EPA-FA or DHA-FA. EPA-200 mg K85EE Tween20 FA DHA-FA ~K85FA preconcentrate (mg) (mg) (mg) (mg)(mg) in 10 ml water A 400 400 100 emulsion B 400 400 100 emulsion C 400300 100 emulsion D 400 300 100 emulsion

Example 10 Pharmaceutical Preconcentrate Composition

A pharmaceutical preconcentrate composition was prepared by mixing thefollowing components:

as the fatty acid oil mixture: K85-EE; in an amount of 10.80 g;

as the surfactant: Tween-20 (Molecular Biology Grade, AppliChemDarmstadt, A4974,0250 lot 5N004174) in an amount of 7.44 g;

as the at least one fatty acid: EPA-FA in an amount of 1.53 g; andDHA-FA in an amount of 1.24 g.

With mixing, a transparent homogenous solution was obtained. The densityof the formulation was determined to be 1.02 g/ml. The composition wasthen filled in vials (vial seize=4 ml) each comprising 1.25×1670 mg=2087mg were prepared, flushed with nitrogen and sealed with parafilm.

Example 11 In Vivo Studies in Mini-Pig

Two different formulations were prepared and sent for in-vivo testing.Formulation 1 was prepared according to Example 10 by mixing thefollowing components: K85EE, Tween20 EPA-FA and DHA-FA in the specifiedamounts, and Formulation 2 was OMACOR gelatine capsules.

The study was performed in 8 male Göttingen SPF minipigs from EllegaardGöttingen Minipigs ApS. The animals were housed individually in floorpens (1.2 m²) with sawdust (“Jeluxyl” from Jelu Werk GmbH, Josef EhrlerGmbH & Co KG, Ludwigsmühle, D-73494 Rosenberg, Germany) as bedding.

Treatment was performed in a cross-over design. The dose was 2 g peranimal. The first day of treatment is designated Day 1. Treatment wasperformed with a wash out period of at least 10 days between eachdosing. Blood samples (n=8) were taken post-dosing. Plasma samples wereanalysed within 2 weeks for total lipid content of EPA and DHA by avalidated LC-MS/MS method. The result presented in FIG. 37 shows theplasma concentration versus time profile of the total lipidconcentration of EPA, supporting supra-bioavailability (e.g., great than40%) for the K85 SMEDDS formulation. A similar results has also beenshown for the time profile of total lipid concentration of DHA (notshown in FIG. 37).

Example 12 Pharmaceutical Formulations, SMEDDs, and SEDDs

Table 28 illustrates pharmaceutical formulations, SMEDDs, and SEDDs thatcan be prepared.

TABLE 28 Pharmaceutical Formulations, SMEDDs, SEDDs Second fatty acidK85FA fatty mixture is a fish oil Reference acid oil Surfactant or ethylester No. mixture Surfactant System concentrate 64 X Tween ® 20 X about40% about 40% about 20% 65 X Tween ® 20 Oleic acid EE 40% 40% 20%

In an embodiment, the surfactant is chosen from among Tween®surfactants, such as 20, 40, 60, 80, and 85. For example, a compositionaccording to the disclosure can include at least one surfactant chosenfrom Tween® 20 and 40.

Example 13 Emulsion/Microemulsion Preconcentrate Formulations

The following emulsion/microemulsions preconcentrate formulationsaccording to the disclosure were prepared.

Pharmaceutical Formulation 1: A SEDDS Composition

A pharmaceutical composition was prepared by mixing the followingcomponents: Fatty acid oil mixture a) EPA-FA in an amount of 5.5 g andDHA-FA in an amount of 4.5 g (achieving approximately the EPA:DHA ratioin a K85EE or FA fatty acid mixture); b) a second fatty acid mixture inEE form: ethyl oleate: Fluka 75100, 137044 50308P14 in an amount of 5.0g; and as the surfactant c): Tween® 20, Molecular Biology Grade,AppliChem Darmstadt, A4974,0250 lot 5N004174 in an amount of 10.0 g.

A transparent homogenous solution was obtained. The density of theformulation was determined to be 1.03 g/ml. The composition was thenfilled into vials (vial size=4 ml) each comprising (2450 mg×1.25)=3063mg were prepared, flushed with nitrogen and sealed with parafilm.

Pharmaceutical Formulation 2

The same formulation as illustrated above was made with Tween® 80,instead of Tween® 20. Thus, mixed fatty acids; EPA-FA (110 mg)+DHA-FA(90 mg), ethyl oleate (100 mg) and Tween 80 (200 mg). A transparenthomogenous solution was obtained.

Example 14 Emulsions in Pure Water

The oil content in one capsule Omacor®, comprising EPA ethyl ester (465mg), DHA ethyl ester (375 mg) and alpha-tocopherol (4 mg) were mixed ina scintillation vial with various surfactants as shown in Table 29.Water (10 ml) was added at 37 degrees centigrade and the mixture wasshaken for 15 seconds using a Vortex mixer. The mixture was observedafter 1 minute and after 5 minutes. The visual score for emulsionhomogeneity was scored as follows: No emulsion=score 0, emulsion but nothomogeneous emulsion=score 1, homogenous emulsion=score 2.

The mixture was after mixing also rolled in a roller mixer for 5minutes. The visual score for this roller test was the same.

TABLE 29 Emulsions in pure water. Score Score After Refer- Amount ofAfter Vortex Score ence Surfactant Vortex for 5 Roller No. Surfactant(s)(mg) 1 minute minutes Mixer 1 None 0 0 0 0 2 Brij ® 30 100 2 2 2 3Brij ® 35 100 2 1 2 4 Brij ® 52 100 2 2 2 5 Brij ® 58 100 2 1 2 6 Brij ®72 100 2 1 2 7 Brij ® 78 100 2 1 2 8 Brij ® 92V 100 2 2 2 9 Brij ® 93100 2 2 2 10 Brij ® 96V 100 2 2 2 11 Brij ® 97 100 2 2 2 12 Brij ® 98100 2 1 2 13 Brij ® 700 100 1 1 2 14 Brij ® S-10 100 1 1 2 15 Pluronic ®L-31 100 1 1 2 16 Pluronic ® L-35 100 1 1 2 17 Pluronic ® L-81 100 2 2 218 Pluronic ® L-64 100 2 2 2 19 Pluronic ® L-121 100 2 2 2 20 Pluronic ®P-123 100 1 1 2 21 Pluronic ® F-68 100 0 0 1 22 Pluronic ® F-108 100 0 01 23 Span ® 20 100 2 2 2 24 Span ® 60 100 0 0 1 25 Span ® 65 100 0 0 026 Span ® 80 100 1 1 2 27 Span ® 85 100 0 0 1 28 Tween ® 20 100 2 1 2 29Tween ® 40 100 2 1 2 30 Tween ® 60 100 2 1 2 31 Tween ® 80 100 2 1 2 32Alginic Acid 100 1 0 1 33 Alginic Acid 100 2 1 1 sodium salt 34Macrogolglycerol- 100 2 2 2 hydroxystearas 40 35 Sodium lauryl 100 1 1 2slphate 36 1,2-Dipalmitoyl- 100 0 0 0 sn-glycerol ethanolamine 371-Hexadecanol 100 1 0 0 38 1,2-Dipalmitoy-sn 100 2 1 1 39 Macrogol 400100 0 0 1 40 Myristic acid 100 1 1 1 sodium salt 41 Brij ® 52/ 30/20 2 22 Macrogolglycerol- hydroxystearas 40 42 Brij ® 62/ 30/50 2 2 2Pluronic ® L64 43 Span ® 40/90 2 2 2 20/Pluronic ® L64 44 Macrogol 400/120/60  2 2 2 Macrogol-glycerol- hydroxystearas 40 45 Tween ® 20/ 60/602 2 2 Span ® 20 46 Tween ® 20/ 90/90/60 2 2 2 Span ® 20/ Macrogol 400 47Span ® 20/ 70/100/40 2 2 2 Tween ® 20/Brij ® 97 48 Alginic acid sodium110/60  2 2 2 salt/Span ® 60 49 Pluronic ® F- 20/180/20 2 2 268/Pluronic ® L64/Span ® 60

Example 15 Emulsions in Artificial Gastric Juice

The oil content in one capsule OMACOR®, comprising EPA ethyl ester (465mg), DHA ethyl ester (375 mg) and alpha-tocopherol (4 mg) were mixed ina scintillation vial with various surfactants as shown in Table 30. Theexperimental set up is the same as described in Example 14 except thatthat artificial gastric juice without pepsin (European Pharmacopeia 6.0,page 274) was used instead of water.

TABLE 30 Emulsions in artificial gastric juice Score Score After afterAmount of Vortex Vortex Score Reference Surfactant for 1 for 5 RollerNo. Surfactant(s) (mg) minute minutes Mixer 50 None 0 0 0 0 51 Brij ® 52100 2 1 2 52 Brij ® 96V 100 2 1 2 53 Pluronic ® L64 100 2 2 2 54 Tween ®40 100 2 2 2 55 Macrogolglycerol- 100 2 2 2 Hydroxysteraras 40

Example 16 Emulsions in Simulated Intestinal Fluid

The oil content in one capsule Omacor®, comprising EPA ethyl ester (465mg), DHA ethyl ester (375 mg) and alpha-tocopherol (4 mg) were mixed ina scintillation vial with various surfactants as shown in Table 31. Theexperimental set up is the same as described in Example 14 except thatsimulated intestinal fluid pH 6.8 without pancreas powder (EuropeanPharmacopeia 6.0, page 274) was used instead of water.

TABLE 31 Emulsions in simulated intestinal fluid. Score Score Afterafter Amount of Vortex Vortex Score Reference Surfactant for 1 for 5Roller No. Surfactant(s) (mg) minute minutes Mixer 56 None 0 0 0 0 57Brij ® 52 100 2 2 2 58 Brij ® 96V 100 2 2 2 59 Pluronic ® L64 100 2 2 260 Tween ® 40 100 2 2 2 61 Macrogolglycerol- 100 2 2 2 Hydroxysteraras40

Example 17 Microscopic Examination of Emulsions

Emulsions from Reference No. 52 (gastric juice) of Example 15 andReference No. 58 (intestinal fluid) of Example 16 were examined underthe microscope after 24 hours rolling. Both emulsions were found to besuspensions of oil in water with no tendency to aggregation.

Example 18 Pharmaceutical Formulations

Table 32 illustrates pharmaceutical formulations that can be prepared.

TABLE 32 Pharmaceutical Formulations K85EE or Reference AGP103 No. OilMixture Surfactant or Surfactant System 64 X Tween ® 20 65 X Tween ® 4066 X Tween ® 80 67 X Tween ® 20 + Tween ® 40 68 X Tween ® + Cremphor ®69 X Tween ® + Solutol HS 15

In an embodiment, the surfactant or combination of surfactants is chosenfrom Tween® surfactants; Tween® 20, Tween® 40, Tween® 60, Tween® 65,Tween® 80 and Tween® 85.

In another embodiment, the surfactant is chosen from a combination of aTween® surfactants and a surfactant chosen from Cremphor®, for instanceTween® 20 and Cremphor EL. Moreover, in a further embodiment, a Tween®20 and Solutol HS 15 surfactant can be used together as well as Tween®20 and Tween® 40.

Fatty acid oil mixtures of pharmaceutical preconcentrates, wherein thefatty acid oil mixture is a K85EE or AGP-103 oil composition arepresented in Table 33.

TABLE 33 Fatty acid oil mixture for pharmaceutical preconcentrates.Fatty acid oil mixture: Maximum 1000 mg K85EE fatty acid oil mixtureMinimum Value Value EPAEE + DHAEE 800 mg/g 880 mg/g EPA EE 430 mg/g 495mg/g DHA EE 347 mg/g 403 mg/g Total omega-3 EE >90% (w/w) EE = ethylester

Example 19 Additional Emulsions in Artificial Gastric Juice andSimulated Intestinal Fluid

Preconcentrates 1-23 were prepared with EPA/DHA ethyl ester (1000 mgK85EE) and various surfactants and surfactant mixtures as shown in Table34. Emulsions were prepared in both gastric juice and simulatedintestinal fluid as described in Examples 15 and 16. Results were thesame for emulsions in artificial gastric juice and simulated intestinalfluid, and appear in Table 34.

TABLE 34 Emulsions in artificial gastric juice and simulated intestinalfluid. Score After Score Ref- Amount of Vortex After Score erenceSurfactant for 1 Vortex 5 Roller No. Surfactant(s) (mg) minute minutesMixer 1 Cremophor ® EL 20 2 1 2 2 Cremophor ® EL 80 2 1 2 3 Cremophor ®EL 100 2 1 2 4 Cremophor ® EL 150 2 2 2 5 Cremophor ® EL 200 2 2 2 6Cremophor ® EL 250 2 2 2 7 Cremophor ® EL 300 2 2 2 8 Cremophor ® EL 4002 2 2 9 Cremophor ® EL 500 2 2 2 10 Cremophor ® EL 600 2 2 2 11Cremophor ® EL 700 2 2 2 12 Cremophor ® EL 800 2 2 2 13 Cremophor ® EL900 2 2 2 14 Cremophor ® EL 1000 2 2 2 15 Cremophor ® EL 1200 2 2 2 16Cremophor ® EL 150 2 2 1 Tween ® 60 100 17 Cremophor ® EL 40 2 2 2Brij ® 30 20 Span ® 85 20 18 Cremophor ® EL 5 2 1 2 19 Cremophor ® EL 602 1 2 Tween ® 80 70 20 Macrogolglyceroli 60 2 1 2 Hydroxystearas 40 21Macrogolglyceroli Hydroxystearas 40 90 2 1 2 Span ® 20 30 Polysorbate 2050 22 Macrogolglyceroli Hydroxystearas 40 60 2 1 2 Brij ® 93 30Polysorbate 20 60 23 Cremophor ® EL 60 2 2 2 Pluronic ® F68 30 Brij ®92V 30 Polysorbate 20 20

Emulsions 4-15 prepared in both artificial gastric juice and simulatedintestinal fluid were homogenous (milky) for several hours whenstanding. Emulsions 1-3 separated somewhat after preparation (i.e.,after several hours of standing). Microscopy of Emulsions 1-15 showedthat the average particle size was less than 100 micrometers.Homogenization treatment (UltraRurrax(IKA)) of Emulsion 4 for 20 secondsresulted in a substantial increase of formation of small particles (<10microns).

Based on the preconcentrates prepared, a 0.5% non-ionic surfactant(e.g., Cremophor®) can emulsify EPA/DHA ethyl ester in both artificialgastric juice and simulated intestinal fluid. In addition, includingmore than one surfactant appears to stabilize the emulsion. Further, theparticle size can vary depending upon the emulsification method.

Example 20 Gelatin Capsules Coated with Cellulose Acetate Phthalate

(A) Gelatin Capsules Comprising EPA Ethyl Ester and DHA Ethyl EsterCoated with Cellulose Acetate Phthalate

Preformed gelatin capsules comprising EPA ethyl ester and DHA ethylester (Omacor®, Pfizer, Norway) were coated by a solution of celluloseacetate phthalate (6%) and triethyl citrate (3%) in acetone. Thecapsules were dried for 24 hour at room temperature. The coatingmaterial (cellulose acetate phthalate plus triethyl citrate) on onecapsule increased the capsule weight by 15 mg.

(B) Gelatin Capsules Comprising EPA ethyl, DHA Ethyl Ester and Brij® 96VCoated with Cellulose Acetate Phthalate

Preformed gelatin capsules comprising EPA ethyl ester (463 mg), DHAethyl ester (375 mg), Brij® 96V (60 mg) and tocoferol (4 mg) were coatedby a solution of cellulose acetate phthalate (6%) and triethyl citrate(3%) in acetone. The capsules were dried for 24 hour at roomtemperature.

Example 21 Gelatin Capsules Coated with Eudragit® RS30D

(A) Gelatin Capsules Comprising EPA Ethyl Ester and DHA Ethyl EsterCoated with Eudragit® RS30D

Preformed gelatin capsules comprising EPA ethyl ester and DHA ethylester (Omacor®, Pfizer, Norway) were coated by an aqueous solution ofEuragit® RS30D from Degussa, Germany. The capsules were dried for 24hour at room temperature.

(B) Gelatin Capsules Comprising EPA Ethyl Ester, DHA Ethyl Ester andBrij® 96V Coated with Eudradit® RS30D

Preformed gelatin capsules comprising EPA ethyl ester (463 mg), DHAethyl ester (375 mg), Brij® 96V (60 mg) and tocopherol (4 mg) werecoated by an aqueous solution of Euragit® RS30D from Degussa, Germany.The capsules were dried for 24 hour at room temperature.

Example 22 Enteric Coated Tablets

Coated tablets were prepared and administered to a animal model(mini-pig) to measure EPA and DHA blood serum levels over time.

Two tablets were pre-treated as follows:

Tablet 31: 20% PEG, 10% Ac-Di-Sol (disintegrant)

Tablet 32: 20% PEG, 0.5 M KH₂PO₄, 10% Ac-Di-Sol (disintegrant)

Pre-treatments were performed in a fluid-bed where the solutions weresprayed on Neusilin granules followed by heating and/or compressing thegranules and incubation in Nitrogen over night before loading with K85EEoil.

Tablets were coated with an inner layer of an aqueous PVA sub-coating(Opadry® II) and an outer layer of an aqueous enteric coating (Acyl EZE(Eudragit® L100-55 enteric coating).

Results for EPA blood serum levels appear in Table 35 and illustrated inFIG. 38. Results for DHA blood serum levels appear in Table 36 andillustrated in FIG. 39.

TABLE 35 EPA blood serum levels AUC [μg/ml] AUC difference dose comparedto K85EE EPA normalised** oil Tablet 31 770.2 8% Tablet 32 672.0 −6%K85EE oil 708.7 reference **AUC data not baseline corrected.

TABLE 36 DHA blood serum levels AUC difference AUC [μg/ml] compared toDHA dosenormalised** K85EE oil Tablet 31 718.1 44% Tablet 32 479.4 −4%K85EE oil 498.8 reference **AUC data not baseline corrected.

The tablets according to the present disclosure may be pre-loaded with apre-concentrate chosen from a K85EE oil+FFA+at least one surfactant(e.g. Tween® 20 or Tween® 80), a K85FA oil+at least one surfactant, andK85EE+at least one surfactant.

1-67. (canceled)
 68. A composition in a gelatin capsule or a tablet formcomprising: a fatty acid oil mixture comprising at least 75%eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight ofthe fatty acid oil mixture, wherein the EPA and DHA are in a form chosenfrom ethyl ester and triglyceride; and at least one free fatty acid;wherein the gelatin capsule or the tablet comprises at least onecoating.
 69. A composition in a gelatin capsule or a tablet formcomprising: a fatty acid oil mixture comprising from about 25% to about75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), byweight of the fatty acid oil mixture, wherein the EPA and DHA are in aform chosen from ethyl ester and triglyceride; and at least one freefatty acid; wherein the gelatin capsule or the tablet comprises at leastone coating.
 70. A method of treating at least one health problem in asubject in need thereof comprising administering to the subject acomposition according to claim 68, wherein the at least one healthproblem is chosen from irregular plasma lipid levels, cardiovascularfunctions, immune functions, visual functions, insulin action, neuronaldevelopment, heart failure, hypertriglyceridemia, hypercholesterolemia,mixed dyslipidemia, dyslipidemia, and post myocardial infarction.
 71. Apreconcentrate in a gelatin capsule or a tablet form comprising: a fattyacid oil mixture comprising at least 75% eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), by weight of the fatty acid oil mixture,wherein the EPA and DHA are in a form chosen from ethyl ester andtriglyceride; at least one free fatty acid; and at least one surfactant;wherein the gelatin capsule or the tablet comprises at least onecoating.
 72. The preconcentrate according to claim 71, wherein thepreconcentrate comprises: from about 45% to about 55% by weight,relative to the weight of the preconcentrate, of the fatty acid oilmixture, wherein the fatty acid oil mixture comprises from about 80% toabout 88% EPA and DHA by weight of the fatty acid oil mixture, and theEPA and DHA are in ethyl ester form; from about 10% to about 15% byweight, relative to the weight of the preconcentrate, of the at leastone free fatty acid, wherein the at least one free fatty acid comprisesfrom about 80% to about 88% EPA and DHA, by weight of the at least onefree fatty acid, and the EPA and DHA are in free fatty acid form; andfrom about 30% to about 40% by weight, relative to the weight of thepreconcentrate, of the at least one surfactant, wherein the at least onesurfactant is chosen from polysorbate 20; further wherein the gelatincapsule or the tablet comprises at least one coating.
 73. Thepreconcentrate according to claim 71, wherein the preconcentratecomprises: from about 45% to about 55% by weight, relative to the weightof the preconcentrate, of the fatty acid oil mixture, wherein the fattyacid oil mixture comprises from about 80% to about 88% EPA and DHA byweight of the fatty acid oil mixture, and the EPA and DHA are in ethylester form; from about 10% to about 15% by weight, relative to theweight of the preconcentrate, of the at least one free fatty acid,wherein the at least one free fatty acid is chosen from oleic acid; andfrom about 30% to about 40% by weight, relative to the weight of thepreconcentrate, of the at least one surfactant, wherein the at least onesurfactant is chosen from polysorbate 20; further wherein the gelatincapsule or the tablet comprises at least one coating.
 74. Thepreconcentrate according to claim 71, wherein the preconcentratecomprises: from about 65% to about 75% by weight, relative to the weightof the preconcentrate, of the fatty acid oil mixture, wherein the fattyacid oil mixture comprises from about 80% to about 88% EPA and DHA byweight of the fatty acid oil mixture, and the EPA and DHA are in ethylester form; from about 15% to about 20% by weight, relative to theweight of the preconcentrate, of the at least one free fatty acid,wherein the at least one free fatty acid is chosen from oleic acid; andfrom about 10% to about 15% by weight, relative to the weight of thepreconcentrate, of the at least one surfactant, wherein the at least onesurfactant is chosen from polysorbate 20; further wherein the gelatincapsule or the tablet comprises at least one coating.
 75. Thepreconcentrate according to claim 71, wherein the preconcentratecomprises: from about 45% to about 55% by weight, relative to the weightof the preconcentrate, of the fatty acid oil mixture, wherein the atleast one fatty acid oil mixture comprises from about 80% to about 88%EPA and DHA by weight of the fatty acid oil mixture, and the EPA and DHAare in ethyl ester form; from about 10% to about 15% by weight, relativeto the weight of the preconcentrate, of the at least one free fattyacid, wherein the at least one free fatty acid comprises from about 80%to about 88% EPA and DHA, by weight of the at least one free fatty acid,and the EPA and DHA are in free fatty acid form; and from about 40% toabout 50% by weight, relative to the weight of the preconcentrate, ofthe at least one surfactant, wherein the at least one surfactantcomprises at least two surfactants chosen from polysorbate 20 andlecithin; further wherein the gelatin capsule or the tablet comprises atleast one coating.
 76. A preconcentrate in a gelatin capsule or a tabletform comprising: a fatty acid oil mixture comprising at least 75%eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by weight ofthe fatty acid oil mixture, wherein the EPA and DHA are in free acidform; and at least one surfactant; wherein the gelatin capsule or thetablet comprises at least one coating.
 77. The preconcentrate accordingto claim 76, wherein the preconcentrate comprises: from about 60% toabout 70% by weight, relative to the weight of the preconcentrate, ofthe fatty acid oil mixture, wherein the at least one fatty acid oilmixture comprises from about 80% to about 88% EPA and DHA, by weight ofthe fatty acid oil mixture, and the EPA and DHA are in free acid form;and from about 30% to about 40% by weight, relative to the weight of thepreconcentrate, of the at least one surfactant, wherein the at least onesurfactant comprises at least two surfactants chosen from polysorbate 20and lecithin; further wherein the gelatin capsule or the tabletcomprises at least one coating.
 78. A preconcentrate in a gelatincapsule or a tablet form comprising: a fatty acid oil mixture comprisingat least 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),by weight of the fatty acid oil mixture, wherein the EPA and DHA are ina form chosen from ethyl ester and triglyceride; and at least onesurfactant; wherein the gelatin capsule or the tablet comprises at leastone coating.
 79. A preconcentrate in a gelatin capsule or a tablet formcomprising: a fatty acid oil mixture comprising from about 25% to about75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), byweight of the fatty acid oil mixture, wherein the EPA and DHA are in aform chosen from ethyl ester and triglyceride; at least one free fattyacid; and at least one surfactant; wherein the gelatin capsule or thetablet comprises at least one coating.
 80. The preconcentrate accordingto claim 79, wherein the preconcentrate comprises from about 300 mg toabout 400 mg of DHA and from about 400 mg to about 500 mg of EPA.
 81. Apreconcentrate in a gelatin capsule or a tablet form comprising: a fattyacid oil mixture comprising from about 25% to about 75% eicosapentaenoicacid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acidoil mixture, wherein the EPA and DHA are in free acid form; and at leastone surfactant; wherein the gelatin capsule or the tablet comprises atleast one coating.
 82. A preconcentrate in a gelatin capsule or a tabletform comprising: a fatty acid oil mixture comprising from about 25% toabout 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), byweight of the fatty acid oil mixture, wherein the EPA and DHA are in aform chosen from ethyl ester and triglyceride; and at least onesurfactant: and wherein the gelatin capsule or the tablet comprises atleast one coating.
 83. A preconcentrate in a gelatin capsule or a tabletform comprising: a fatty acid oil mixture comprising eicosapentaenoicacid (EPA) and docosahexaenoic acid (DHA), by weight of the fatty acidoil mixture, wherein the EPA and DHA are in a form chosen from ethylester, triglyceride, and free fatty acid, and are present in the fattyacid oil mixture at a weight ratio ranging from about 1:10 to about10:1; and oleic acid; at least one surfactant chosen from polysorbate 20and polysorbate 80; at least one antioxidant; and wherein the gelatincapsule or the tablet comprises at least one coating.
 84. Aself-nanoemulsifying drug delivery system (SNEDDS),self-microemulsifying drug delivery system (SMEDDS), or self-emulsifyingdrug delivery system (SEDDS) comprising a preconcentrate according toany one of claims 71, 76, and 78, wherein the preconcentrate forms anemulsion in an aqueous solution.
 85. A method of treating at least onehealth problem in a subject in need thereof comprising administering tothe subject a pharmaceutical preconcentrate according to any one ofclaims 71, 76, and 78, wherein the at least one health problem is chosenfrom irregular plasma lipid levels, cardiovascular functions, immunefunctions, visual functions, insulin action, neuronal development, heartfailure, hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia,dyslipidemia, and post myocardial infarction.
 86. A method of treatingat least one health problem in a subject in need thereof comprisingadministering to the subject a self-nanoemulsifying drug delivery system(SNEDDS), self-microemulsifying drug delivery system (SMEDDS), orself-emulsifying drug delivery system (SEDDS) according to claim 84,wherein the at least one health problem is chosen from irregular plasmalipid levels, cardiovascular functions, immune functions, visualfunctions, insulin action, neuronal development, heart failure,hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia,dyslipidemia, and post myocardial infarction.
 87. The compositionaccording to any one of claims 68 and 69, wherein the EPA and DHA arepresent in the fatty acid oil mixture at a weight ratio ranging fromabout 1:10 to about 10:1, from about 1:8 to about 8:1, from about 1:7 toabout 7:1, from about 1:6 to about 6:1, from about 1:5 to about 5:1,from about 1:4 to about 4:1, from about 1:3 to about 3:1, from about 1:2to about 2:1, from about 1:1 to about 2:1, or from about 1:2 to about1:3.
 88. The preconcentrate according to any one of claims 71, 76, 78,79, 81, and 82, wherein the EPA and DHA are present in the fatty acidoil mixture at a weight ratio ranging from about 1:10 to about 10:1,from about 1:8 to about 8:1, from about 1:7 to about 7:1, from about 1:6to about 6:1, from about 1:5 to about 5:1, from about 1:4 to about 4:1,from about 1:3 to about 3:1, from about 1:2 to about 2:1, from about 1:1to about 2:1, or from about 1:2 to about 1:3.
 89. A composition in agelatin capsule or a tablet form comprising: a fatty acid oil mixturecomprising eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),wherein the EPA and DHA are in a form chosen from ethyl ester andtriglyceride; and at least one free fatty acid; wherein the gelatincapsule or the tablet comprises at least one coating; and furtherwherein the EPA and DHA are present in the fatty acid oil mixture at aweight ratio ranging from about 1:10 to about 10:1, from about 1:8 toabout 8:1, from about 1:7 to about 7:1, from about 1:6 to about 6:1,from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3to about 3:1, from about 1:2 to about 2:1, from about 1:1 to about 2:1,or from about 1:2 to about 1:3.
 90. The composition according to claim89, wherein the EPA:DHA weight ratio of the fatty acid oil mixtureranges from about 1:7 to about 7:1.
 91. The composition according toclaim 89, wherein the EPA:DHA weight ratio of the fatty acid oil mixturecomprises about 4:2.
 92. A preconcentrate in a gelatin capsule or atablet form comprising: a fatty acid oil mixture comprisingeicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), wherein theEPA and DHA are in a form chosen from ethyl ester, triglyceride, andfree fatty acid; at least one free fatty acid; and at least onesurfactant; wherein the gelatin capsule or the tablet comprises at leastone coating; and further wherein the EPA and DHA are present in thefatty acid oil mixture at a weight ratio ranging from about 1:10 toabout 10:1, from about 1:8 to about 8:1, from about 1:7 to about 7:1,from about 1:6 to about 6:1, from about 1:5 to about 5:1, from about 1:4to about 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1,from about 1:1 to about 2:1, or from about 1:2 to about 1:3.
 93. Thepreconcentrate according to claim 92, wherein the preconcentratecomprises: from about 45% to about 55% by weight, relative to the weightof the preconcentrate, of the fatty acid oil mixture comprising EPA andDHA, wherein the EPA and DHA are in ethyl ester form; from about 10% toabout 15% by weight, relative to the weight of the preconcentrate, ofthe at least one free fatty acid, wherein the at least one free fattyacid comprises from about 80% to about 88% EPA and DHA, by weight of theat least one free fatty acid, and the EPA and DHA are in free fatty acidform; and from about 30% to about 40% by weight, relative to the weightof the preconcentrate, of the at least one surfactant, wherein the atleast one surfactant is chosen from polysorbate 20; wherein the gelatincapsule or the tablet comprises at least one coating; and furtherwherein the EPA and DHA are present in the fatty acid oil mixture at aweight ratio ranging from about 1:10 to about 10:1, from about 1:8 toabout 8:1, from about 1:7 to about 7:1, from about 1:6 to about 6:1,from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3to about 3:1, from about 1:2 to about 2:1, from about 1:1 to about 2:1,or from about 1:2 to about 1:3.
 94. The preconcentrate according toclaim 92, wherein the preconcentrate comprises: from about 45% to about55% by weight, relative to the weight of the preconcentrate, of thefatty acid oil mixture comprising EPA and DHA, wherein the EPA and DHAare in ethyl ester form; from about 10% to about 15% by weight, relativeto the weight of the preconcentrate, of the at least one free fattyacid, wherein the at least one free fatty acid is chosen from oleicacid; and from about 30% to about 40% by weight, relative to the weightof the preconcentrate, of the at least one surfactant, wherein the atleast one surfactant is chosen from polysorbate 20; wherein the gelatincapsule or the tablet comprises at least one coating; and furtherwherein the EPA and DHA are present in the fatty acid oil mixture at aweight ratio ranging from about 1:10 to about 10:1, from about 1:8 toabout 8:1, from about 1:7 to about 7:1, from about 1:6 to about 6:1,from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3to about 3:1, from about 1:2 to about 2:1, from about 1:1 to about 2:1,or from about 1:2 to about 1:3.
 95. The preconcentrate according toclaim 92, wherein the preconcentrate comprises: from about 65% to about75% by weight, relative to the weight of the preconcentrate, of thefatty acid oil mixture comprising EPA and DHA, wherein the EPA and DHAare in ethyl ester form; from about 15% to about 20% by weight, relativeto the weight of the preconcentrate, of the at least one free fattyacid, wherein the at least one free fatty acid is chosen from oleicacid; and from about 10% to about 15% by weight, relative to the weightof the preconcentrate, of the at least one surfactant, wherein the atleast one surfactant is chosen from polysorbate 20; wherein the gelatincapsule or the tablet comprises at least one coating; and furtherwherein the EPA and DHA are present in the fatty acid oil mixture at aweight ratio ranging from about 1:10 to about 10:1, from about 1:8 toabout 8:1, from about 1:7 to about 7:1, from about 1:6 to about 6:1,from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3to about 3:1, from about 1:2 to about 2:1, from about 1:1 to about 2:1,or from about 1:2 to about 1:3.
 96. The preconcentrate according toclaim 92, wherein the preconcentrate comprises: from about 45% to about55% by weight, relative to the weight of the preconcentrate, of thefatty acid oil mixture comprising EPA and DHA, wherein the EPA and DHAare in ethyl ester form; from about 10% to about 15% by weight, relativeto the weight of the preconcentrate, of the at least one free fattyacid, wherein the at least one free fatty acid comprises from about 80%to about 88% EPA and DHA, by weight of the at least one free fatty acid,and the EPA and DHA are in free fatty acid form; and from about 40% toabout 50% by weight, relative to the weight of the preconcentrate, ofthe at least one surfactant, wherein the at least one surfactantcomprises at least two surfactants chosen from polysorbate 20 andlecithin; wherein the gelatin capsule or the tablet comprises at leastone coating; and further wherein the EPA and DHA are present in thefatty acid oil mixture at a weight ratio ranging from about 1:10 toabout 10:1, from about 1:8 to about 8:1, from about 1:7 to about 7:1,from about 1:6 to about 6:1, from about 1:5 to about 5:1, from about 1:4to about 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1,from about 1:1 to about 2:1, or from about 1:2 to about 1:3.
 97. Apreconcentrate in a gelatin capsule or a tablet form comprising: a fattyacid oil mixture comprising eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), by weight of the fatty acid oil mixture,wherein the EPA and DHA are in free acid form; and at least onesurfactant; wherein the gelatin capsule or the tablet comprises at leastone coating; and further wherein the EPA and DHA are present in thefatty acid oil mixture at a weight ratio ranging from about 1:10 toabout 10:1, from about 1:8 to about 8:1, from about 1:7 to about 7:1,from about 1:6 to about 6:1, from about 1:5 to about 5:1, from about 1:4to about 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1,from about 1:1 to about 2:1, or from about 1:2 to about 1:3.
 98. Thepreconcentrate according to claim 97, wherein the preconcentratecomprises: from about 60% to about 70% by weight, relative to the weightof the preconcentrate, of the fatty acid oil mixture comprising EPA andDHA, wherein the EPA and DHA are in free acid form; and from about 30%to about 40% by weight, relative to the weight of the preconcentrate, ofthe at least one surfactant, wherein the at least one surfactantcomprises at least two surfactants chosen from polysorbate 20 andlecithin; wherein the gelatin capsule or the tablet comprises at leastone coating; and further wherein the EPA and DHA are present in thefatty acid oil mixture at a weight ratio ranging from about 1:10 toabout 10:1, from about 1:8 to about 8:1, from about 1:7 to about 7:1,from about 1:6 to about 6:1, from about 1:5 to about 5:1, from about 1:4to about 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1,from about 1:1 to about 2:1, or from about 1:2 to about 1:3.
 99. Apreconcentrate in a gelatin capsule or a tablet form comprising: a fattyacid oil mixture comprising eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), by weight of the fatty acid oil mixture,wherein the EPA and DHA are in a form chosen from ethyl ester andtriglyceride; and at least one surfactant; wherein the gelatin capsuleor the tablet comprises at least one coating; and further wherein theEPA and DHA are present in the fatty acid oil mixture at a weight ratioranging from about 1:10 to about 10:1, from about 1:8 to about 8:1, fromabout 1:7 to about 7:1, from about 1:6 to about 6:1, from about 1:5 toabout 5:1, from about 1:4 to about 4:1, from about 1:3 to about 3:1,from about 1:2 to about 2:1, from about 1:1 to about 2:1, or from about1:2 to about 1:3.
 100. The preconcentrate according to claim 99, whereinthe preconcentrate comprises: from about 75% to about 85% by weight,relative to the weight of the preconcentrate, of the fatty acid oilmixture comprising EPA and DHA, wherein the EPA and DHA are in ethylester form; and from about 15% to about 25% by weight, relative to theweight of the preconcentrate, of the at least one surfactant, whereinthe at least one surfactant is chosen from polysorbate 80; wherein thegelatin capsule or the tablet comprises at least one coating; andfurther wherein the EPA and DHA are present in the fatty acid oilmixture at a weight ratio ranging from about 1:10 to about 10:1, fromabout 1:8 to about 8:1, from about 1:7 to about 7:1, from about 1:6 toabout 6:1, from about 1:5 to about 5:1, from about 1:4 to about 4:1,from about 1:3 to about 3:1, from about 1:2 to about 2:1, from about 1:1to about 2:1, or from about 1:2 to about 1:3.
 101. The preconcentrateaccording to any one of claims 92, 97, and 99, wherein the EPA:DHAweight ratio of the fatty acid oil mixture ranges from about 1:7 toabout 7:1.
 102. A self-nanoemulsifying drug delivery system (SNEDDS),self-microemulsifying drug delivery system (SMEDDS), or self-emulsifyingdrug delivery system (SEDDS) comprising a preconcentrate according toany one of claims 92, 97, and 99, wherein the preconcentrate forms anemulsion in an aqueous solution.
 103. The preconcentrate according toclaim 71, further comprising at least one antioxidant.
 104. Thepreconcentrate according to claim 103, wherein: the fatty acid oilmixture comprises about 84% EPA and DHA, by weight of the fatty acid oilmixture, wherein the EPA and DHA are in an ethyl ester form; the atleast one surfactant comprises polysorbate 20; the at least one freefatty acid comprises oleic acid; and the at least one antioxidantcomprises butylhydroxyanisoles (BHA).
 105. The preconcentrate accordingto claim 76, further comprising at least one antioxidant.
 106. Thepreconcentrate according to claim 105, wherein: the fatty acid oilmixture comprises about 84% EPA and DHA, by weight of the fatty acid oilmixture, wherein the EPA and DHA are in free acid form; the at least onesurfactant comprises polysorbate 20 and macrogol 15 hydroxystearate; andthe at least one antioxidant comprises butylhydroxyanisoles (BHA). 107.A composition according to claim 90, wherein the fatty acid oil mixturecomprises at least 75% EPA and DHA, by weight of the fatty acid oilmixture.
 108. A composition in a gelatin capsule or a tablet formcomprising: a fatty acid oil mixture comprising eicosapentaenoic acid(EPA) and docosahexaenoic acid (DHA), by weight of the fatty acid oilmixture, wherein the EPA and DHA are in free acid form; and at least onesurfactant; wherein the gelatin capsule or the tablet comprises at leastone coating; and further wherein the EPA and DHA are present in thefatty acid oil mixture at a weight ratio ranging from about 1:10 toabout 10:1, from about 1:8 to about 8:1, from about 1:7 to about 7:1,from about 1:6 to about 6:1, from about 1:5 to about 5:1, from about 1:4to about 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1,from about 1:1 to about 2:1, or from about 1:2 to about 1:3.
 109. Thecomposition according to claim 108, wherein the fatty acid oil mixturecomprises at least 65% EPA and DHA, by weight of the fatty acid oilmixture, and further wherein the EPA and DHA are present in the fattyacid oil mixture at a weight ratio ranging from about 1:4 to about 4:1.110. The preconcentrate according to claim 71, wherein the EPA and DHAare in ethyl ester form; and at least 95% of the at least 75% EPA andDHA of the fatty acid oil mixture is EPA.
 111. The preconcentrateaccording to claim 71, wherein the EPA and DHA are in ethyl ester form;and at least 95% of the at least 75% EPA and DHA of the fatty acid oilmixture is DHA.
 112. The composition according to any one of claim 68,wherein the at least one coating is chosen from enteric coatings,sub-layers, top-layers, and combinations thereof.
 113. The compositionaccording to claim 112, wherein the gelatin capsule or tablet comprisesat least one enteric coating.
 114. The composition according to claim113, wherein the gelatin capsule or tablet further comprises at leastone top-layer above the enteric coating and at least one sub-layerbetween the gelatin capsule wall or tablet surface and the entericcoating, wherein the at least one sub-layer comprises a sealant. 115.The composition according to claim 112, wherein the at least one coatingcomprises at least one material chosen from gelatin, film-formingagents, polymers, and copolymers between methacrylic acid and methylmethacrylate, copolymers between methacrylic acid and methyl acrylate,copolymers between methacrylic acid and ethyl methacrylate, copolymersbetween methacrylic acid and ethyl acrylate, cellulose acetatephthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, andmixtures thereof.
 116. The composition according to claim 112, whereinthe at least one coating is pH-dependent or pH-independent.
 117. Thecomposition according to claim 112, wherein the at least one coatingcomprises at least one plasticizer chosen from triethyl citrate,triacetin, polyethylene glycol, propylene glycol, phthalates, sorbitol,glycerin, and mixtures thereof.
 118. The composition according to claim112, wherein the gelatin capsule is a hard capsule or a soft capsule.119. The composition according to claim 112, wherein the gelatin capsulefill content ranges from about 0.400 g to about 1.300 g, from about0.600 g to about 1.200 g, or from about 0.800 g to about 1.000 g. 120.The composition according to claim 112, wherein the gelatin capsule ortablet releases less than 30% of the total EPA and DHA in the stomach.121. The preconcentrate according to any one of claim 71, wherein the atleast one coating is chosen from enteric coatings, sub-layers,top-layers, and combinations thereof.
 122. The preconcentrate accordingto claim 121, wherein the gelatin capsule or tablet comprises at leastone enteric coating.
 123. The preconcentrate according to claim 122,wherein the gelatin capsule or tablet further comprises at least onetop-layer above the enteric coating and at least one sub-layer betweenthe gelatin capsule wall or tablet surface and the enteric coating,wherein the at least one sub-layer comprises a sealant.
 124. Thepreconcentrate according to claim 121, wherein the at least one coatingcomprises at least one material chosen from gelatin, film-formingagents, polymers, and copolymers between methacrylic acid and methylmethacrylate, copolymers between methacrylic acid and methyl acrylate,copolymers between methacrylic acid and ethyl methacrylate, copolymersbetween methacrylic acid and ethyl acrylate, cellulose acetatephthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, andmixtures thereof.
 125. The preconcentrate according to claim 121,wherein the at least one coating is pH-dependent or pH-independent. 126.The preconcentrate according to claim 121, wherein the at least onecoating comprises at least one plasticizer chosen from triethyl citrate,triacetin, polyethylene glycol, propylene glycol, phthalates, sorbitol,glycerin, and mixtures thereof.
 127. The preconcentrate according toclaim 121, wherein the gelatin capsule is a hard capsule or a softcapsule.
 128. The preconcentrate according to claim 121, wherein thegelatin capsule fill content ranges from about 0.400 g to about 1.300 g,from about 0.600 g to about 1.200 g, or from about 0.800 g to about1.000 g.
 129. The preconcentrate according to claim 121, wherein thegelatin capsule or tablet releases less than 30% of the total EPA andDHA in the stomach.
 130. The preconcentrate according to any one ofclaim 71, wherein the at least one surfactant is chosen from polysorbate20, polysorbate 40, polysorbate 60, polysorbate 80, and mixturesthereof.
 131. The preconcentrate according to any one of claim 71,wherein the EPA and DHA are present in the fatty acid oil mixture at aweight ratio ranging from about 1:2 to about 2:1.